CN107205961A - The prodrug of phenols TRPV1 activators - Google Patents

The prodrug of phenols TRPV1 activators Download PDF

Info

Publication number
CN107205961A
CN107205961A CN201580074440.4A CN201580074440A CN107205961A CN 107205961 A CN107205961 A CN 107205961A CN 201580074440 A CN201580074440 A CN 201580074440A CN 107205961 A CN107205961 A CN 107205961A
Authority
CN
China
Prior art keywords
compound
formula
alkyl
substituted
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201580074440.4A
Other languages
Chinese (zh)
Other versions
CN107205961B (en
Inventor
克雷格·休斯菲尔德
约翰·F·多诺万
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Concentric Analgesia Drug Cos
Concentric Analgesics Inc
Original Assignee
Concentric Analgesia Drug Cos
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Concentric Analgesia Drug Cos filed Critical Concentric Analgesia Drug Cos
Publication of CN107205961A publication Critical patent/CN107205961A/en
Application granted granted Critical
Publication of CN107205961B publication Critical patent/CN107205961B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A61P23/02—Local anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/40—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings
    • C07C271/42—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/52—Esters of carbamic acids having oxygen atoms of carbamate groups bound to carbon atoms of six-membered aromatic rings with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/195—Radicals derived from nitrogen analogues of carboxylic acids

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Virology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Communicable Diseases (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Oncology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Endocrinology (AREA)
  • Anesthesiology (AREA)
  • Immunology (AREA)
  • Obesity (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Dermatology (AREA)
  • Reproductive Health (AREA)
  • AIDS & HIV (AREA)
  • Molecular Biology (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Pharmaceutical composition and medicine this document describes compound, comprising such compound, and the method for adjusting using such compound the acceptor (TRPV1) of transient receptor potential class Vanillin 1 activity.

Description

The prodrug of phenols TRPV1 activators
Cross reference
This application claims the rights and interests for the U.S. Provisional Application No. 62/084,515 for being filed on November 25th, 2014, and It is the continuation application for the U.S. Patent Application No. 14/743,375 for being filed on June 18th, 2015, the two is by reference It is incorporated by with it in this.
Background of invention
Pharmaceutical composition and medicine this document describes compound, comprising such compound, and use suchization The method of acceptor (TRPV1) activity of compound regulation transient receptor potential class Vanillin 1.
The content of the invention
On the one hand, this document describes the compound with formula (I) structure：
Wherein：
Y is phenols TRPV1 activators, and the hydrogen atom of wherein phenolic hydroxy group is bonded to-C (O)-X- (C (R1)(R2))n- Z's Covalent bond is replaced；
X is-C (R1)(R2)-、-O-、-N(R5)-or-S-；
N is 1 to 10 integer；
Z is-NR3R4Or-CO2H；
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base, Huo Zhexiang R on adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl；And
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；
Or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (I) in one embodiment, wherein Y isR6Independently selected from hydrogen, Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,- C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluothane Base, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl Sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For substituted or unsubstituted alkane Base.It is the compound of formula (I) in another embodiment, wherein Y isR6Independently selected from hydrogen, halogen Element ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, Miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl are sub- Sulfone, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For unsubstituted alkyl or it is selected from The alkyl of one or more substituent groups of the following group：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkane Base ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, Aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.It is in another embodiment The compound of formula (I), wherein Y isR6For alkoxy；J is-NHC (O) R7Or-C (O) OR7；And R7For Unsubstituted alkyl or be selected from the following group one or more substituent groups alkyl：Halogen ,-CN ,-NH2、-NH(CH3)、-N (CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, fluothane oxygen Base, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and virtue Base sulfone.It is the compound of formula (I) in another embodiment, wherein Y isR6For alkoxy；J is-NHC (O)R7Or-C (O) OR7；And R7For unsubstituted alkyl.
It is the compound of formula (I) in some embodiments, wherein Y is
In some embodiment party It is the compound of formula (I) in case, wherein Z is-NR3R4.In some embodiments be formula (I) compound, wherein Z for- NR3R4；R3For hydrogen；And R4For H, or substituted or unsubstituted alkyl.It is the compound of formula (I) in some embodiments, its Middle X is-N (R5)-.It is the compound of formula (I) in some embodiments, wherein X is-N (R5R on)-, and adjacent atom1 And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl.In some embodiments For formula (I) compound, wherein X is-N (R5R on)-, and adjacent atom1And R5The atom one that group is attached together with them Rise and form substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted pyrrolidines Ring, substituted or unsubstituted piperidine ring, or substituted or unsubstituted piperazine ring.It is the chemical combination of formula (I) in some embodiments Thing, wherein Y areIt is the compound of formula (I) in some embodiments, its With structure
It is the compound of formula (I) in some embodiments, wherein Y is
In some embodiment party It is the compound of formula (I) in case, wherein Z is-NR3R4.In some embodiments be formula (I) compound, wherein Z for- NR3R4；R3For hydrogen；And R4For H, or substituted or unsubstituted alkyl.It is the compound of formula (I) in some embodiments, its Middle X is-N (R5)-.It is the compound of formula (I) in some embodiments, wherein X is-N (R5)-and R5To replace or not taking The alkyl in generation.It is the compound of formula (I) in some embodiments, wherein X is-N (R5)-and R5For unsubstituted alkyl. It is the compound of formula (I) in some embodiments, wherein X is-N (R5)-and R5For-CH3.It is formula in some embodiments (I) compound, wherein X are-N (R5)-and R5For substituted alkyl.It is the compound of formula (I) in some embodiments, Wherein X is-N (R5)-and R5For-CH2CH2NH2.It is the compound of formula (I) in some embodiments, wherein X is-N (R5)- And R5For-CH2CH2NH (alkyl).It is the compound of formula (I) in some embodiments, wherein X is-O-.In some implementations It is the compound of formula (I) in scheme, wherein X is-C (R1)(R2)-.It is the compound of formula (I), wherein n in some embodiments For 2 to 6 integer.It is the compound of formula (I) in some embodiments, wherein n is 2.It is formula (I) in some embodiments Compound, wherein n be 3.It is the compound of formula (I) in some embodiments, wherein n is 4.
It is the compound of formula (I) in some embodiments, it has formula (II) structure：
Wherein Z is-NR3R4, and n is 2 to 10 integer.It is the compound of formula (II) in some embodiments, wherein Y isR6Independently selected from hydrogen, halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkane Base ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, Aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For substituted or unsubstituted alkyl.It is the compound of formula (II) in some embodiments, wherein Y isR6Independently selected from hydrogen, halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkane Base ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, Aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For unsubstituted alkyl or the alkyl for the one or more substituent groups for being selected from the following group：Halogen ,-CN ,-NH2、- NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl )2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alcoxyl Base, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, Alkyl sulfone and aryl sulfone.It is the compound of formula (II) in some embodiments, wherein Y isR6For alcoxyl Base；J is-NHC (O) R7Or-C (O) OR7；And R7For unsubstituted alkyl or it is selected from one or more substituent groups of the following group Alkyl：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkanes Base, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, aryl sulphur Generation, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.It is the compound of formula (II) in some embodiments, wherein Y isR6For alkoxy；J is-NHC (O) R7Or-C (O) OR7；And R7For unsubstituted alkyl.In some realities The compound for formula (II) in scheme is applied, wherein Y is
In some embodiment party It is the compound of formula (II) in case, it has formula (IIa) structure：
Wherein p is 1 to 9 integer.It is the compound of formula (IIa) in some embodiments, it has formula (IIaa) structure：
It is the compound of formula (II), (IIa) or (IIaa), the wherein R on adjacent atom in some embodiments1And R5Group The atom being attached together with them forms substituted or unsubstituted heterocycloalkyl.It is formula in some embodiments (II), (IIa) or (IIaa) compound, the wherein R on adjacent atom1And R5The atom shape that group is attached together with them Into substituted or unsubstituted heterocycloalkyl, and the heterocycloalkyl is substituted or unsubstituted pyrrolidine ring, taken Generation or unsubstituted piperidine ring, or substituted or unsubstituted piperazine ring.In some embodiments for formula (II), (IIa) or (IIaa) R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substitution or not taken The heterocycloalkyl in generation；The heterocycloalkyl is substituted or unsubstituted pyrrolidine ring, substituted or unsubstituted piperidines Ring, or substituted or unsubstituted piperazine ring；R3For hydrogen；And R4For hydrogen or methyl.Be in some embodiments formula (II), (IIa) or (IIaa) compound, the wherein R on adjacent atom1And R5The atom that group is attached together with them forms substitution Or unsubstituted heterocycloalkyl；The heterocycloalkyl is substituted or unsubstituted pyrrolidine ring, substitution or unsubstituted Piperidine ring, or substituted or unsubstituted piperazine ring；R3For hydrogen；And R4For hydrogen.Be in some embodiments formula (II), (IIa) or (IIaa) compound, the wherein R on adjacent atom1And R5The atom that group is attached together with them forms substitution Or unsubstituted heterocycloalkyl；The heterocycloalkyl is substituted or unsubstituted pyrrolidine ring, substitution or unsubstituted Piperidine ring, or substituted or unsubstituted piperazine ring；R3For hydrogen；And R4For methyl.Be in some embodiments formula (II), (IIa) or (IIaa) compound, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1 to 9 integer.
It is the compound of formula (II), (IIa) or (IIaa) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1 to 9 integer.
It is the compound of formula (II) in some embodiments, it has formula (IIb) structure：
Wherein p is 1 to 9 integer.It is the compound of formula (IIb) in some embodiments, it has formula (IIbb) structure：
It is in some embodiments formula (IIb) or the compound of (IIbb), the wherein R on adjacent atom1And R5Group connects The atom being attached with them forms substituted or unsubstituted heterocycloalkyl together.It is formula (IIb) in some embodiments Or the compound of (IIbb), the wherein R on adjacent atom1And R5The atom that group is attached together with them formed substitution or not Substituted heterocycloalkyl, and the heterocycloalkyl is substituted or unsubstituted pyrrolidine ring, substitution or unsubstituted Piperidine ring, or substituted or unsubstituted piperazine ring.It is in some embodiments formula (IIb) or the compound of (IIbb), its Middle R3For hydrogen and R4For hydrogen or methyl.It is in some embodiments formula (IIb) or the compound of (IIbb), wherein R3For hydrogen And R4For hydrogen.
It is the compound of formula (IIa), (IIaa), (IIb) or (IIbb) in some embodiments, wherein p is 1.One It is the compound of formula (IIa), (IIaa), (IIb) or (IIbb) in a little embodiments, wherein p is 2.
It is the compound of formula (I) in some embodiments, it has formula (III) structure：
It is the compound of formula (III) in some embodiments, wherein Y isR6Independently selected from Hydrogen, halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkane Base) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, Fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, Alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7To be substituted or unsubstituted Alkyl.It is the compound of formula (III) in some embodiments, wherein Y isR6Independently selected from hydrogen, Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,- C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluothane Base, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl Sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For unsubstituted alkyl or selected From the alkyl of one or more substituent groups of the following group：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2 Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, Aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.It is in some embodiments The compound of formula (III), wherein Y isR6For alkoxy；J is-NHC (O) R7Or-C (O) OR7；And R7 For unsubstituted alkyl or the alkyl for the one or more substituent groups for being selected from the following group：Halogen ,-CN ,-NH2、-NH(CH3)、-N (CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, fluothane oxygen Base, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and virtue Base sulfone.It is the compound of formula (III) in some embodiments, wherein Y isR6For alkoxy；J for- NHC(O)R7Or-C (O) OR7；And R7For unsubstituted alkyl.It is the compound of formula (III) in some embodiments, wherein Y is
In some embodiment party It is the compound of formula (III) in case, it has formula (IIIa) structure：
Wherein p is 0 to 9 integer.It is the compound of formula (IIIa) in some embodiments, it has formula (IIIaa) knot Structure：
It is the compound of formula (III) in some embodiments, it has formula (IIIb) structure：
Wherein p is 0 to 9 integer.It is the compound of formula (IIIb) in some embodiments, it has formula (IIIbb) knot Structure：
For any and whole embodiment as described herein, substituent is selected from the subset of listed alternate item.
It is the compound of formula (III), (IIIa), (IIIaa), (IIIb) or (IIIbb) in some embodiments, wherein Each R1With each R2It is hydrogen.It is formula (III), (IIIa), (IIIaa), (IIIb) or (IIIbb) in some embodiments Compound, wherein at least one R1For substituted or unsubstituted alkyl.Be in some embodiments formula (IIIa), (IIIaa), (IIIb) or (IIIbb) compound, wherein p is 0.In some embodiments for formula (IIIa), (IIIaa), (IIIb) or (IIIbb) compound, wherein p be 1.In some embodiments for formula (IIIa), (IIIaa), (IIIb) or (IIIbb) compound, wherein p are 2.
On the other hand be a kind of pharmaceutical composition, its comprising formula (I), (II), (IIa), (IIaa), (IIb), (IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、 (IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、 (IIIff), (IV), (V) or (VI) compound, or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or Hydrate, and pharmaceutically acceptable diluent, excipient or adhesive.In some embodiments, by the medicine group Compound is formulated for being injected intravenously, is subcutaneously injected, intramuscular injection, intraperitoneal injection, neural surrounding injection, axon (neuraxial) injection, intra-articular injection, orally administer or local application.
It is on the other hand the method for the pain for treating subject, it includes applying therapeutically effective amount to the subject Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、 (IIIdd), the compound of (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its is pharmaceutically acceptable Salt, pharmaceutically acceptable solvate or hydrate.It is in some embodiments the method for the pain for treating subject, It include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、 (IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、(IV)、(V) Or the compound of (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the pain Pain and postoperative pain, chronic postsurgical pain, neuropathic pain, postherpetic neuralgia, diabetic neuropathy, HIV phases Close DPN, it is complex region pain syndrome, cancer, neurotrosis, cancer chemotherapy, Vulvodynia, wound, operation, chronic Musculoskeletal pain, back pain, osteoarthritis or rheumatoid arthritis are relevant.It is in some embodiments treatment subject Pain method, it include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、 (IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、 (IIIff), (IV), (V) or (VI) compound, or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or Hydrate, wherein the compound local application, dermal administration, applied dermally or systemic administration.
Embodiment
Main component --- the capsaicine of Chili pepper (chili pepper) pungent taste is produced, is in capsicum (Capsicum) a kind of alkaloid found in family.Capsaicine (8- methy-N-vanillyl -6- nonenamides) is to be directed to part The non-selective cation channel of gate --- the acceptor (TRPV1 of transient receptor potential class Vanillin 1；It is referred to as class before fragrant Careless element acceptor (VR1)) high selectivity activator.TRPV1 is preferential in minor diameter sensory neuron, particularly special detection pain Or expressed in harmful those A fibers felt and fiber C.TRPV1 is to harmful including capsaicine, heat and extracellular acidification Stimulation is reacted, and exposure is combined while stimulating these.(Caterina M J,Julius D.The vanilloid receptor:a molecular gateway to the pain pathway.Annu Rev Neurosci.2001.24:487-517)。
It was demonstrated that TRPV1 activators such as capsaicine mitigate pain in a variety of environment, but it is related in the presence of being used to it Problem.The initial action of (capsaicin sensitive) nociceptor activation of TRPV1 expression is burn feeling, hyperalgia, different Perseverance pain and erythema.However, long-time exposed to low concentration capsaicine or single exposure in high concentration capsaicine or other After TRPV1 activators, minor diameter sensation neurite becomes less sensitive to a variety of stimulations including capsaicine or thermostimulation.This Plant exposure for a long time and be further characterized in that pain reaction mitigates.These late-actings of capsaicine are commonly referred to as " desensitizing ", and Be the various pain syndromes for the treatment of seek peace other situations capsaicine formulation development general principle.(Bley,K.R.Recent developments in transient receptor potential vanilloid receptor 1agonist- based therapies.Expert Opin Investig Drugs.2004.13(11):1445-1456)。
In addition, capsaicine and other TRPV1 activators have very limited amount of water solubility, it is to need special set in processing The stimulant of standby very strength, and due to its limited aqueous solubility, thus be not easy with as aqueous solution obtain it is common Medicine is mixed.Therefore, the use of non-aqueous based formulations is necessary to delivering enough capsaicines or other TRPV1 activators.These systems Agent is often mismatched with current practice/program, especially for the aseptic aqueous solution used in operation.Further, since capsicum The ability for causing stimulation of plain strength, therefore will preferably use makes capsaicine live before prodrug reaches expectation active site Property minimize capsaicine water-soluble prodrug.
Therefore, it would be desirable to provide TRPV1 activator prodrugs, it has：1) improve water solubility, 2) reduction or delay with TRPV1 activators apply the potentiality of related excitant (pungency), and 3) (TRPV1 activators are passed in a fast manner Half-life period is sent within 30min) or the ability that delivers of the mode (TRPV1 activators deliver half-life period more than 30min) that delays.Separately Outside, it may be desirable to delay the beginning of pro-drug conversion using chemicals/additive.In addition, it would be desirable to predictive role position The TRPV1 activator prodrugs for dissolving in aqueous sterile injectable preparation are provided.Finally, in some cases, it would be desirable to together with peppery Green pepper element prodrug or other TRPV1 activator prodrugs are delivered together the compound of another pharmacologically activity, particularly local fiber crops Liquor-saturated dose.
Therefore, compound as described herein is related to the new type water-solubility prodrug of TRPV1 activators and its synthesis and used Method.These prodrugs TRPV1 agonist derivatives are recovered to active parent compound when exposed to physiological conditions.Describedization Compound has significantly higher hydrophily/water solubility than its parent drug, therefore can more be impregnated in conventional aqueous formulation.Herein Further describe by using hydrophilic parts modify parent molecule chemical constitution come improve capsaicine, its analog and other The water miscible method of TRPV1 activators.In some embodiments as described herein, it can be protonated in acid condition The introducing of basic moiety improve the solubility of TRPV1 prodrugs.In some embodiments as described herein, by increasing capacitance it is possible to increase total The introducing of the acidic moiety of body hydrophilic characteristics improves the solubility of TRPV1 prodrugs.Devise prodrug as described herein so that Body is delivered in the prodrug and/or after specific physiological conditions, and parent drug is anti-via cyclisation release It should be discharged with the speed clearly limited.The Chemical releases dynamics of parent drug can assign two it is important the characteristics of：(a) due to pushing away Avoiding for injecting amount TRPV1 activator rapid deliveries and potential reduction and/or the excitant that delays, and (b) parent TRPV1 excitements Agent is from prodrug is quick or sustained release, for the regulation of specific pharmacological activity/result.Such structural modification eliminate in order to 1) adapt to many TRPV1 activators/Capsaicinoids (capsaicinoid) low-down water-soluble and 2) reduction with TRPV1 activators are using related Acute irritation test to the dependence of preparation or the particular/special requirement of delivery apparatus.In addition, working as and it When his medicine is delivered jointly, especially when via injection apply it is a variety of without microbial inoculum when, water-soluble prodrug is desired.
Capsaicine as described herein, Capsaicinoids or other TRPV1 activator prodrugs are modified by sulphation to control Capsaicine, Capsaicinoids or other TRPV1 activators are stated by intramolecular cyclization release reaction that pH is controlled and biology can Speed.In some embodiments, TRPV1 activators prodrug as described herein is in the pH levels for being adapted to prepare pharmaceutical preparation The lower stability with extension, but the degradation in vivo in a controlled manner under physiological conditions.After parenteral administration, formula (I)、(II)、(IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、 (IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、 (IIIdd), the cyclisation that the compound of (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) is controlled via pH Release reaction changes into parent drug (TRPV1 activators).The speed of pro-drug conversion determines by cyclisation release reaction, can be by adding Plus buffer solution changes the cyclisation release reaction.In some embodiments, the buffer solution provides time window, wherein until Return to before physiological status, the conversion to parent drug is significantly slowed.In some embodiments, parent drug is adjusted Release, quick release is provided with the speed discharged based on intramolecular cyclization.In some embodiments, releasing for parent drug is adjusted Put, sustained release is provided with the speed discharged based on intramolecular cyclization.In some embodiments as described herein, the parent Medicine is discharged (D=TRPV1 activators) by the intramolecular cyclization based on amine：
In some embodiments as described herein, the parent drug discharges (D by the intramolecular cyclization based on carboxylate =TRPV1 activators)：
In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 10 seconds to 10 hours.One In a little embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 10 seconds to 1 hour.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 10 seconds to 30 minutes.In some embodiments, 37 DEG C, under pH 7.4 Cyclisation speed (t1/2) between 1 minute to 10 hours.In some embodiments, 37 DEG C, the cyclisation speed under pH 7.4 (t1/2) between 1 minute to 30 minutes.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) at 2 minutes To between 30 minutes.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) 5 minutes to 30 minutes it Between.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 2 minutes to 15 minutes.In some realities Apply in scheme, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 5 minutes to 15 minutes.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 15 minutes to 2 hours.In some embodiments, 37 DEG C, under pH 7.4 Cyclisation speed (t1/2) between 15 minutes to 1.5 hours.In some embodiments, 37 DEG C, the cyclisation speed under pH 7.4 (t1/2) between 15 minutes to 1 hour.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) at 30 points Clock is between 2 hours.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) at 30 minutes to 1.5 hours Between.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 30 minutes to 1 hour.At some In embodiment, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 1 hour to 4 hours.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 1 hour to 3 hours.In some embodiments, 37 DEG C, under pH 7.4 It is cyclized speed (t1/2) between 1 hour to 2 hours.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) Between 2 hours to 10 hours.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) small at 2 hours to 6 When between.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 2 hours to 4 hours.At some In embodiment, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 2 hours to 3 hours.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 3 hours to 5 hours.In some embodiments, 37 DEG C, under pH 7.4 It is cyclized speed (t1/2) between 4 hours to 6 hours.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) Between 5 hours to 7 hours.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) small at 6 hours to 8 When between.In some embodiments, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 7 hours to 9 hours.At some In embodiment, 37 DEG C, the cyclisation speed (t under pH 7.41/2) between 8 hours to 10 hours.
Compound
On the one hand, this document describes the compound with formula (I) structure：
Wherein：
Y is phenols TRPV1 activators, and the hydrogen atom of wherein phenolic hydroxy group is bonded to-C (O)-X- (C (R1)(R2))n- Z's Covalent bond is replaced；
X is-C (R1)(R2)-、-O-、-N(R5)-or-S-；
N is 1 to 10 integer；
Z is-NR3R4Or-CO2H；
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base, Huo Zhexiang R on adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl；And
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
For any and whole embodiment, substituent is selected from the subset of listed alternate item.For example, in some realities The compound for formula (I) in scheme is applied, wherein Z is-NR3R4.In other embodiments be formula (I) compound, wherein Z for- CO2H。
It is the compound of formula (I) in some embodiments, wherein Y isR6Independently selected from hydrogen, Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,- C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluothane Base, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl Sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For substituted or unsubstituted alkane Base.It is the compound of formula (I) in some embodiments, wherein Y isR6Independently selected from hydrogen, halogen ,- CN、-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkane Base, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, virtue Base sulfoxide, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For unsubstituted alkyl or it is selected from the following group One or more substituent groups alkyl：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,- C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, fragrant oxygen Base, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.It is formula (I) in some embodiments Compound, wherein Y isR6For alkoxy；J is-NHC (O) R7Or-C (O) OR7；And R7To be unsubstituted Alkyl or be selected from the following group one or more substituent groups alkyl：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、- OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (= O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, heterocycle alkane Base, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.One It is the compound of formula (I) in a little embodiments, wherein Y isR6For alkoxy；J is-NHC (O) R7Or-C (O)OR7；And R7For unsubstituted alkyl.
It is the compound of formula (I) in some embodiments, wherein Y is
In some embodiment party It is the compound of formula (I) in case, wherein Y is
It is the compound of formula (I) in some embodiments, wherein Y isIt is the compound of formula (I) in some embodiments, wherein Y is
It is the compound of formula (I) in some embodiments, wherein Y isIt is the compound of formula (I) in some embodiments, wherein Y is
It is the compound of formula (I) in some embodiments, wherein X is-O-.It is in some embodiments formula (I) Compound, wherein X are-S-.It is the compound of formula (I) in some embodiments, wherein X is-C (R1)(R2)-.In some realities The compound for formula (I) in scheme is applied, wherein X is-C (R1)(R2)-and R1And R2It is each independently hydrogen, substitution or does not take The alkyl in generation, or substituted or unsubstituted aryl.It is the compound of formula (I) in some embodiments, wherein X is-CH2-. It is the compound of formula (I) in some embodiments, wherein X is-CH (CH3)-.It is the chemical combination of formula (I) in some embodiments Thing, wherein X are-C (CH3)2-.It is the compound of formula (I) in some embodiments, wherein X is-C (R1)(R2)-, and phase Two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted cycloalkyl base Group.It is the compound of formula (I) in some embodiments, wherein X is-N (R5)-.It is the change of formula (I) in some embodiments Compound, wherein X are-N (R5)-and R5For substituted or unsubstituted alkyl.It is the compound of formula (I) in some embodiments, Wherein X is-N (R5)-and R5For unsubstituted alkyl.It is the compound of formula (I) in some embodiments, wherein X is-N (R5)-and R5For substituted alkyl.It is the compound of formula (I) in some embodiments, wherein X is-N (R5)-and R5For Substituted or unsubstituted aryl.It is the compound of formula (I) in some embodiments, wherein X is-N (R5)-and R5For substitution Phenyl.It is the compound of formula (I) in some embodiments, wherein X is-N (R5)-and R5For unsubstituted phenyl.One It is the compound of formula (I) in a little embodiments, wherein X is-NH-.It is the compound of formula (I), wherein X in some embodiments For-N (CH3)-.It is the compound of formula (I) in some embodiments, wherein X is-N (CH2CH3)-.In some embodiments For formula (I) compound, wherein X is-N (CH2CH2NH2)-.In some embodiments be formula (I) compound, wherein X for- N(CH2CH2NH (alkyl))-.It is the compound of formula (I) in some embodiments, wherein X is-N (CH2CH2NH(CH3))-. It is the compound of formula (I) in the further embodiment of any foregoing embodiments, wherein Z is-CO2H.In any foregoing implementation It is the compound of formula (I) in the another embodiment of scheme, wherein Z is-NR3R4.In another implementation of any foregoing embodiments It is the compound of formula (I) in scheme, wherein Z is-NR3R4And R3And R4It is each independently hydrogen, or substituted or unsubstituted alkane Base.Compound in the another embodiment of any foregoing embodiments for formula (I), wherein Z is-NR3R4And R3And R4Respectively From independently being hydrogen or methyl.In the another embodiment of any foregoing embodiments be formula (I) compound, wherein Z for- NR3R4And R3And R4It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (I), wherein Z For-NR3R4And R3For hydrogen or R4For methyl.Chemical combination in the another embodiment of any foregoing embodiments for formula (I) Thing, wherein n are 1.Compound in the another embodiment of any foregoing embodiments for formula (I), wherein n is 2.Any It is the compound of formula (I) in the another embodiment of foregoing embodiments, wherein n is 3.In the another of any foregoing embodiments It is the compound of formula (I) in embodiment, wherein n is 4.It is formula (I) in the another embodiment of any foregoing embodiments Compound, wherein n be 5.Compound in the another embodiment of any foregoing embodiments for formula (I), wherein n is 6. Compound in the another embodiment of any foregoing embodiments for formula (I), wherein n is 7.In any foregoing embodiments Another embodiment in be formula (I) compound, wherein n be 8.It is in the another embodiment of any foregoing embodiments The compound of formula (I), wherein n is 9.Compound in the another embodiment of any foregoing embodiments for formula (I), wherein N is 10.
In another embodiment, this document describes the compound with formula (II) structure：
Wherein：
Y is phenols TRPV1 activators, and the hydrogen atom of wherein phenolic hydroxy group is bonded to-C (O)-N (R5)-(C(R1)(R2))n- Z covalent bond is replaced；
Z is-NR3R4；
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base, Huo Zhexiang R on adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
N is 2 to 10 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (II) in some embodiments, wherein Y isR6Independently selected from hydrogen, Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,- C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluothane Base, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl Sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For substituted or unsubstituted alkane Base.It is the compound of formula (II) in some embodiments, wherein Y isR6Independently selected from hydrogen, halogen Element ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, Miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl are sub- Sulfone, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For unsubstituted alkyl or it is selected from The alkyl of one or more substituent groups of the following group：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkane Base ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, Aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.It is in some embodiments The compound of formula (II), wherein Y isR6For alkoxy；J is-NHC (O) R7Or-C (O) OR7；And R7For Unsubstituted alkyl or be selected from the following group one or more substituent groups alkyl：Halogen ,-CN ,-NH2、-NH(CH3)、-N (CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, fluothane oxygen Base, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and virtue Base sulfone.It is the compound of formula (II) in some embodiments, wherein Y isR6For alkoxy；J is-NHC (O)R7Or-C (O) OR7；And R7For unsubstituted alkyl.
It is the compound of formula (II) in some embodiments, wherein Y is
In some embodiment party It is the compound of formula (II) in case, wherein Y is
It is the compound of formula (II) in some embodiments, wherein Y isIt is the compound of formula (II) in some embodiments, wherein Y is
It is the compound of formula (II) in some embodiments, wherein Y isIt is the compound of formula (II) in some embodiments, wherein Y is
It is the compound of formula (II), wherein R in some embodiments5For H.It is in some embodiments formula (II) Compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (II), wherein R in some embodiments5For not Substituted alkyl.It is the compound of formula (II), wherein R in some embodiments5For substituted alkyl.In some embodiments In be formula (II) compound, wherein R5For substituted or unsubstituted aryl.It is the chemical combination of formula (II) in some embodiments Thing, wherein R5For substituted phenyl.It is the compound of formula (II), wherein R in some embodiments5For unsubstituted phenyl. It is the compound of formula (II), wherein R in some embodiments5For-CH3.It is the compound of formula (II) in some embodiments, Wherein R5For-CH2CH3.It is the compound of formula (II), wherein R in some embodiments5For-CH2CH2NH2.In some implementations It is the compound of formula (II), wherein R in scheme5For-CH2CH2NH (alkyl).It is the chemical combination of formula (II) in some embodiments Thing, wherein R5For-CH2CH2NH(CH3).Compound in the another embodiment of any foregoing embodiments for formula (II), Wherein each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.Before any The compound for formula (II) in the another embodiment of embodiment is stated, wherein each R1And R2It is each independently hydrogen, or substitution Or unsubstituted alkyl.Compound in the another embodiment of any foregoing embodiments for formula (II), wherein each R1 And R2It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (II), wherein adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base.Any It is the compound of formula (II), the wherein R on adjacent atom in the another embodiment of foregoing embodiments1And R5Group is together with it The atom that is attached form substituted or unsubstituted heterocycloalkyl together.In another embodiment party of any foregoing embodiments It is the compound of formula (II), wherein R in case3And R4It is each independently hydrogen, or substituted or unsubstituted alkyl.Any foregoing It is the compound of formula (II), wherein R in the another embodiment of embodiment3And R4It is each independently hydrogen or methyl.Any It is the compound of formula (II), wherein R in the another embodiment of foregoing embodiments3And R4It is hydrogen.In any foregoing embodiment party It is the compound of formula (II), wherein R in the another embodiment of case3For hydrogen or R4For methyl.In the another of any foregoing embodiments It is the compound of formula (II) in one embodiment, wherein n is 2.It is formula in the another embodiment of any foregoing embodiments (II) compound, wherein n are 3.Compound in the another embodiment of any foregoing embodiments for formula (II), wherein N is 4.Compound in the another embodiment of any foregoing embodiments for formula (II), wherein n is 5.In any foregoing reality The compound for formula (II) in the another embodiment of scheme is applied, wherein n is 6.In another implementation of any foregoing embodiments It is the compound of formula (II) in scheme, wherein n is 7.It is formula (II) in the another embodiment of any foregoing embodiments Compound, wherein n are 8.Compound in the another embodiment of any foregoing embodiments for formula (II), wherein n is 9. Compound in the another embodiment of any foregoing embodiments for formula (II), wherein n is 10.
In another embodiment, this document describes the compound with formula (IIa) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base, Huo Zhexiang R on adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIa), wherein R in some embodiments5For H.It is formula (IIa) in some embodiments Compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IIa), wherein R in some embodiments5For Unsubstituted alkyl.It is the compound of formula (IIa), wherein R in some embodiments5For substituted alkyl.In some implementations It is the compound of formula (IIa), wherein R in scheme5For substituted or unsubstituted aryl.It is formula (IIa) in some embodiments Compound, wherein R5For substituted phenyl.It is the compound of formula (IIa), wherein R in some embodiments5To be unsubstituted Phenyl.It is the compound of formula (IIa), wherein R in some embodiments5For-CH3.It is formula (IIa) in some embodiments Compound, wherein R5For-CH2CH3.It is the compound of formula (IIa), wherein R in some embodiments5For-CH2CH2NH2。 It is the compound of formula (IIa), wherein R in some embodiments5For-CH2CH2NH (alkyl).It is formula in some embodiments (IIa) compound, wherein R5For-CH2CH2NH(CH3).It is formula in the another embodiment of any foregoing embodiments (IIa) compound, wherein each R1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or it is substituted or unsubstituted Aryl.Compound in the another embodiment of any foregoing embodiments for formula (IIa), wherein each R1And R2Each solely It is on the spot hydrogen, or substituted or unsubstituted alkyl.Change in the another embodiment of any foregoing embodiments for formula (IIa) Compound, wherein each R1And R2It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IIa), Wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In another implementation of any foregoing embodiments It is the compound of formula (IIa), wherein two on adjacent carbon atom R in scheme1Or R2The carbon atom one that group is attached together with them Rise and form substituted or unsubstituted group of naphthene base.It is formula (IIa) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group.Compound in the another embodiment of any foregoing embodiments for formula (IIa), wherein on adjacent atom R1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl, wherein the heterocycle alkane Base group is substituted or unsubstituted pyrrolidine ring.It is formula (IIa) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring.In the another of any foregoing embodiments It is the compound of formula (IIa), the wherein R on adjacent atom in embodiment1And R5The atom shape that group is attached together with them Into substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperazine ring.It is in office It is the compound of formula (IIa), wherein R in the another embodiment for foregoing embodiments of anticipating3And R4Hydrogen is each independently, or is taken Generation or unsubstituted alkyl.Compound in the another embodiment of any foregoing embodiments for formula (IIa), wherein R3With R4It is each independently hydrogen or methyl.Compound in the another embodiment of any foregoing embodiments for formula (IIa), its Middle R3And R4It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IIa), wherein R3For hydrogen Or R4For methyl.Compound in the another embodiment of any foregoing embodiments for formula (IIa), wherein p is 1.It is in office It is the compound of formula (IIa) in the another embodiment for foregoing embodiments of anticipating, wherein p is 2.In any foregoing embodiments It is the compound of formula (IIa) in another embodiment, wherein p is 3.It is in the another embodiment of any foregoing embodiments The compound of formula (IIa), wherein p is 4.Compound in the another embodiment of any foregoing embodiments for formula (IIa), Wherein p is 5.Compound in the another embodiment of any foregoing embodiments for formula (IIa), wherein p is 6.Any It is the compound of formula (IIa) in the another embodiment of foregoing embodiments, wherein p is 7.In the another of any foregoing embodiments It is the compound of formula (IIa) in one embodiment, wherein p is 8.It is formula in the another embodiment of any foregoing embodiments (IIa) compound, wherein p are 9.
In another embodiment, this document describes the compound with formula (IIaa) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and R1And R2It is each independently hydrogen, takes Generation or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or R1And R5Group is together with it The atom that is attached form substituted or unsubstituted heterocycloalkyl together；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIaa), wherein R in some embodiments5For H.It is formula in some embodiments (IIaa) compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IIaa) in some embodiments, Wherein R5For unsubstituted alkyl.It is the compound of formula (IIaa), wherein R in some embodiments5For substituted alkyl. It is the compound of formula (IIaa), wherein R in some embodiments5For substituted or unsubstituted aryl.In some embodiments For formula (IIaa) compound, wherein R5For substituted phenyl.It is the compound of formula (IIaa) in some embodiments, wherein R5For unsubstituted phenyl.It is the compound of formula (IIaa), wherein R in some embodiments5For-CH3.In some embodiment party It is the compound of formula (IIaa), wherein R in case5For-CH2CH3.It is the compound of formula (IIaa) in some embodiments, wherein R5For-CH2CH2NH2.It is the compound of formula (IIaa), wherein R in some embodiments5For-CH2CH2NH (alkyl).One It is the compound of formula (IIaa), wherein R in a little embodiments5For-CH2CH2NH(CH3).In the another of any foregoing embodiments It is the compound of formula (IIaa), wherein R in embodiment1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or is taken Generation or unsubstituted aryl.Compound in the another embodiment of any foregoing embodiments for formula (IIaa), wherein R1 And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is in the another embodiment of any foregoing embodiments The compound of formula (IIaa), wherein R1And R2For hydrogen.It is formula (IIaa) in the another embodiment of any foregoing embodiments Compound, wherein R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another of any foregoing embodiments It is the compound of formula (IIaa), the wherein R on adjacent atom in embodiment1And R5The atom that group is attached together with them Form substituted or unsubstituted heterocycloalkyl.It is formula (IIaa) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group, wherein the heterocycloalkyl is substituted or unsubstituted pyrrolidine ring.In the another of any foregoing embodiments It is the compound of formula (IIaa), the wherein R on adjacent atom in one embodiment1And R5The atom one that group is attached together with them Rise and form substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring. Compound in the another embodiment of any foregoing embodiments for formula (IIaa), the wherein R on adjacent atom1And R5Base The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is Substituted or unsubstituted piperazine ring.Compound in the another embodiment of any foregoing embodiments for formula (IIaa), its Middle R3And R4It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another embodiment of any foregoing embodiments For formula (IIaa) compound, wherein R3And R4It is each independently hydrogen or methyl.In another implementation of any foregoing embodiments It is the compound of formula (IIaa), wherein R in scheme3And R4It is hydrogen.It is in the another embodiment of any foregoing embodiments The compound of formula (IIaa), wherein R3For hydrogen or R4For methyl.It is formula in the another embodiment of any foregoing embodiments (IIaa) compound, wherein p are 1.Compound in the another embodiment of any foregoing embodiments for formula (IIaa), Wherein p is 2.Compound in the another embodiment of any foregoing embodiments for formula (IIaa), wherein p is 3.Any It is the compound of formula (IIaa) in the another embodiment of foregoing embodiments, wherein p is 4.In any foregoing embodiments It is the compound of formula (IIaa) in another embodiment, wherein p is 5.In the another embodiment of any foregoing embodiments For formula (IIaa) compound, wherein p is 6.Change in the another embodiment of any foregoing embodiments for formula (IIaa) Compound, wherein p are 7.Compound in the another embodiment of any foregoing embodiments for formula (IIaa), wherein p is 8. Compound in the another embodiment of any foregoing embodiments for formula (IIaa), wherein p is 9.
It is the compound of formula (IIaa) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1 to 9 integer.
It is the compound of formula (IIaa) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1 to 2 integer.
It is the compound of formula (IIaa) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1.
It is the compound of formula (IIaa) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 2.
It is the compound of formula (IIaa) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1 to 9 integer.
It is the compound of formula (IIaa) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1 to 2 integer.
It is the compound of formula (IIaa) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1.
It is the compound of formula (IIaa) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 2.
In another embodiment, this document describes the compound with formula (IIb) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base, Huo Zhexiang R on adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIb), wherein R in some embodiments5For H.It is formula (IIb) in some embodiments Compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IIb), wherein R in some embodiments5For Unsubstituted alkyl.It is the compound of formula (IIb), wherein R in some embodiments5For substituted alkyl.In some implementations It is the compound of formula (IIb), wherein R in scheme5For substituted or unsubstituted aryl.It is formula (IIb) in some embodiments Compound, wherein R5For substituted phenyl.It is the compound of formula (IIb), wherein R in some embodiments5To be unsubstituted Phenyl.It is the compound of formula (IIb), wherein R in some embodiments5For-CH3.It is formula (IIb) in some embodiments Compound, wherein R5For-CH2CH3.It is the compound of formula (IIb), wherein R in some embodiments5For-CH2CH2NH2。 It is the compound of formula (IIb), wherein R in some embodiments5For-CH2CH2NH (alkyl).It is formula in some embodiments (IIb) compound, wherein R5For-CH2CH2NH(CH3).It is formula in the another embodiment of any foregoing embodiments (IIb) compound, wherein each R1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or it is substituted or unsubstituted Aryl.Compound in the another embodiment of any foregoing embodiments for formula (IIb), wherein each R1And R2Each solely It is on the spot hydrogen, or substituted or unsubstituted alkyl.Change in the another embodiment of any foregoing embodiments for formula (IIb) Compound, wherein each R1And R2It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IIb), Wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In another implementation of any foregoing embodiments It is the compound of formula (IIb), wherein two on adjacent carbon atom R in scheme1Or R2The carbon atom one that group is attached together with them Rise and form substituted or unsubstituted group of naphthene base.It is formula (IIb) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group.Compound in the another embodiment of any foregoing embodiments for formula (IIb), wherein on adjacent atom R1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl, wherein the heterocycle alkane Base group is substituted or unsubstituted pyrrolidine ring.It is formula (IIb) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring.In the another of any foregoing embodiments It is the compound of formula (IIb), the wherein R on adjacent atom in embodiment1And R5The atom shape that group is attached together with them Into substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperazine ring.It is in office It is the compound of formula (IIb), wherein R in the another embodiment for foregoing embodiments of anticipating3And R4Hydrogen is each independently, or is taken Generation or unsubstituted alkyl.Compound in the another embodiment of any foregoing embodiments for formula (IIb), wherein R3With R4It is each independently hydrogen or methyl.Compound in the another embodiment of any foregoing embodiments for formula (IIb), its Middle R3And R4It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IIb), wherein R3For hydrogen Or R4For methyl.Compound in the another embodiment of any foregoing embodiments for formula (IIb), wherein p is 1.It is in office It is the compound of formula (IIb) in the another embodiment for foregoing embodiments of anticipating, wherein p is 2.In any foregoing embodiments It is the compound of formula (IIb) in another embodiment, wherein p is 3.It is in the another embodiment of any foregoing embodiments The compound of formula (IIb), wherein p is 4.Compound in the another embodiment of any foregoing embodiments for formula (IIb), Wherein p is 5.Compound in the another embodiment of any foregoing embodiments for formula (IIb), wherein p is 6.Any It is the compound of formula (IIb) in the another embodiment of foregoing embodiments, wherein p is 7.In the another of any foregoing embodiments It is the compound of formula (IIb) in one embodiment, wherein p is 8.It is formula in the another embodiment of any foregoing embodiments (IIb) compound, wherein p are 9.
In another embodiment, this document describes the compound with formula (IIbb) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and R1And R2It is each independently hydrogen, takes Generation or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or R1And R5Group is together with it The atom that is attached form substituted or unsubstituted heterocycloalkyl together；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIbb), wherein R in some embodiments5For H.It is formula in some embodiments (IIbb) compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IIbb) in some embodiments, Wherein R5For unsubstituted alkyl.It is the compound of formula (IIbb), wherein R in some embodiments5For substituted alkyl. It is the compound of formula (IIbb), wherein R in some embodiments5For substituted or unsubstituted aryl.In some embodiments For formula (IIbb) compound, wherein R5For substituted phenyl.It is the compound of formula (IIbb) in some embodiments, wherein R5For unsubstituted phenyl.It is the compound of formula (IIbb), wherein R in some embodiments5For-CH3.In some embodiment party It is the compound of formula (IIbb), wherein R in case5For-CH2CH3.It is the compound of formula (IIbb) in some embodiments, wherein R5For-CH2CH2NH2.It is the compound of formula (IIbb), wherein R in some embodiments5For-CH2CH2NH (alkyl).One It is the compound of formula (IIbb), wherein R in a little embodiments5For-CH2CH2NH(CH3).In the another of any foregoing embodiments It is the compound of formula (IIbb), wherein R in embodiment1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or is taken Generation or unsubstituted aryl.Compound in the another embodiment of any foregoing embodiments for formula (IIbb), wherein R1 And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is in the another embodiment of any foregoing embodiments The compound of formula (IIbb), wherein R1And R2For hydrogen.It is formula (IIbb) in the another embodiment of any foregoing embodiments Compound, wherein R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another of any foregoing embodiments It is the compound of formula (IIbb), the wherein R on adjacent atom in embodiment1And R5The atom that group is attached together with them Form substituted or unsubstituted heterocycloalkyl.It is formula (IIbb) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group, wherein the heterocycloalkyl is substituted or unsubstituted pyrrolidine ring.In the another of any foregoing embodiments It is the compound of formula (IIbb), the wherein R on adjacent atom in one embodiment1And R5The atom one that group is attached together with them Rise and form substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring. Compound in the another embodiment of any foregoing embodiments for formula (IIbb), the wherein R on adjacent atom1And R5Base The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is Substituted or unsubstituted piperazine ring.Compound in the another embodiment of any foregoing embodiments for formula (IIbb), its Middle R3And R4It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another embodiment of any foregoing embodiments For formula (IIbb) compound, wherein R3And R4It is each independently hydrogen or methyl.In another implementation of any foregoing embodiments It is the compound of formula (IIbb), wherein R in scheme3And R4It is hydrogen.It is in the another embodiment of any foregoing embodiments The compound of formula (IIbb), wherein R3For hydrogen or R4For methyl.It is formula in the another embodiment of any foregoing embodiments (IIbb) compound, wherein p are 1.Compound in the another embodiment of any foregoing embodiments for formula (IIbb), Wherein p is 2.Compound in the another embodiment of any foregoing embodiments for formula (IIbb), wherein p is 3.Any It is the compound of formula (IIbb) in the another embodiment of foregoing embodiments, wherein p is 4.In any foregoing embodiments It is the compound of formula (IIbb) in another embodiment, wherein p is 5.In the another embodiment of any foregoing embodiments For formula (IIbb) compound, wherein p is 6.Change in the another embodiment of any foregoing embodiments for formula (IIbb) Compound, wherein p are 7.Compound in the another embodiment of any foregoing embodiments for formula (IIbb), wherein p is 8. Compound in the another embodiment of any foregoing embodiments for formula (IIbb), wherein p is 9.
It is the compound of formula (IIbb) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1 to 9 integer.
It is the compound of formula (IIbb) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1 to 2 integer.
It is the compound of formula (IIbb) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1.
It is the compound of formula (IIbb) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 2.
It is the compound of formula (IIbb) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1 to 9 integer.
It is the compound of formula (IIbb) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1 to 2 integer.
It is the compound of formula (IIbb) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 1.
It is the compound of formula (IIbb) in some embodiments, it has following structure：
Wherein R4For hydrogen or methyl；And p is 2.
In another embodiment, this document describes the compound with formula (IIc) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base, Huo Zhexiang R on adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIc), wherein R in some embodiments5For H.It is formula (IIc) in some embodiments Compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IIc), wherein R in some embodiments5For Unsubstituted alkyl.It is the compound of formula (IIc), wherein R in some embodiments5For substituted alkyl.In some implementations It is the compound of formula (IIc), wherein R in scheme5For substituted or unsubstituted aryl.It is formula (IIc) in some embodiments Compound, wherein R5For substituted phenyl.It is the compound of formula (IIc), wherein R in some embodiments5To be unsubstituted Phenyl.It is the compound of formula (IIc), wherein R in some embodiments5For-CH3.It is formula (IIc) in some embodiments Compound, wherein R5For-CH2CH3.It is the compound of formula (IIc), wherein R in some embodiments5For-CH2CH2NH2。 It is the compound of formula (IIc), wherein R in some embodiments5For-CH2CH2NH (alkyl).It is formula in some embodiments (IIc) compound, wherein R5For-CH2CH2NH(CH3).It is formula in the another embodiment of any foregoing embodiments (IIc) compound, wherein each R1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or it is substituted or unsubstituted Aryl.Compound in the another embodiment of any foregoing embodiments for formula (IIc), wherein each R1And R2Each solely It is on the spot hydrogen, or substituted or unsubstituted alkyl.Change in the another embodiment of any foregoing embodiments for formula (IIc) Compound, wherein each R1And R2It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IIc), Wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In another implementation of any foregoing embodiments It is the compound of formula (IIc), wherein two on adjacent carbon atom R in scheme1Or R2The carbon atom one that group is attached together with them Rise and form substituted or unsubstituted group of naphthene base.It is formula (IIc) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group.Compound in the another embodiment of any foregoing embodiments for formula (IIc), wherein on adjacent atom R1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl, wherein the heterocycle alkane Base group is substituted or unsubstituted pyrrolidine ring.It is formula (IIc) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring.In the another of any foregoing embodiments It is the compound of formula (IIc), the wherein R on adjacent atom in embodiment1And R5The atom shape that group is attached together with them Into substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperazine ring.It is in office It is the compound of formula (IIc), wherein R in the another embodiment for foregoing embodiments of anticipating3And R4Hydrogen is each independently, or is taken Generation or unsubstituted alkyl.Compound in the another embodiment of any foregoing embodiments for formula (IIc), wherein R3With R4It is each independently hydrogen or methyl.Compound in the another embodiment of any foregoing embodiments for formula (IIc), its Middle R3And R4It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IIc), wherein R3For hydrogen Or R4For methyl.Compound in the another embodiment of any foregoing embodiments for formula (IIc), wherein p is 1.It is in office It is the compound of formula (IIc) in the another embodiment for foregoing embodiments of anticipating, wherein p is 2.In any foregoing embodiments It is the compound of formula (IIc) in another embodiment, wherein p is 3.It is in the another embodiment of any foregoing embodiments The compound of formula (IIc), wherein p is 4.Compound in the another embodiment of any foregoing embodiments for formula (IIc), Wherein p is 5.Compound in the another embodiment of any foregoing embodiments for formula (IIc), wherein p is 6.Any It is the compound of formula (IIc) in the another embodiment of foregoing embodiments, wherein p is 7.In the another of any foregoing embodiments It is the compound of formula (IIc) in one embodiment, wherein p is 8.It is formula in the another embodiment of any foregoing embodiments (IIc) compound, wherein p are 9.
In another embodiment, this document describes the compound with formula (IIcc) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and R1And R2It is each independently hydrogen, takes Generation or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or R1And R5Group is together with it The atom that is attached form substituted or unsubstituted heterocycloalkyl together；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIcc), wherein R in some embodiments5For H.It is formula in some embodiments (IIcc) compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IIcc) in some embodiments, Wherein R5For unsubstituted alkyl.It is the compound of formula (IIcc), wherein R in some embodiments5For substituted alkyl. It is the compound of formula (IIcc), wherein R in some embodiments5For substituted or unsubstituted aryl.In some embodiments For formula (IIcc) compound, wherein R5For substituted phenyl.It is the compound of formula (IIcc) in some embodiments, wherein R5For unsubstituted phenyl.It is the compound of formula (IIcc), wherein R in some embodiments5For-CH3.In some embodiment party It is the compound of formula (IIcc), wherein R in case5For-CH2CH3.It is the compound of formula (IIcc) in some embodiments, wherein R5For-CH2CH2NH2.It is the compound of formula (IIcc), wherein R in some embodiments5For-CH2CH2NH (alkyl).One It is the compound of formula (IIcc), wherein R in a little embodiments5For-CH2CH2NH(CH3).In the another of any foregoing embodiments It is the compound of formula (IIcc), wherein R in embodiment1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or is taken Generation or unsubstituted aryl.Compound in the another embodiment of any foregoing embodiments for formula (IIcc), wherein R1 And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is in the another embodiment of any foregoing embodiments The compound of formula (IIcc), wherein R1And R2For hydrogen.It is formula (IIcc) in the another embodiment of any foregoing embodiments Compound, wherein R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another of any foregoing embodiments It is the compound of formula (IIcc), the wherein R on adjacent atom in embodiment1And R5The atom that group is attached together with them Form substituted or unsubstituted heterocycloalkyl.It is formula (IIcc) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group, wherein the heterocycloalkyl is substituted or unsubstituted pyrrolidine ring.In the another of any foregoing embodiments It is the compound of formula (IIcc), the wherein R on adjacent atom in one embodiment1And R5The atom one that group is attached together with them Rise and form substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring. Compound in the another embodiment of any foregoing embodiments for formula (IIcc), the wherein R on adjacent atom1And R5Base The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is Substituted or unsubstituted piperazine ring.Compound in the another embodiment of any foregoing embodiments for formula (IIcc), its Middle R3And R4It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another embodiment of any foregoing embodiments For formula (IIcc) compound, wherein R3And R4It is each independently hydrogen or methyl.In another implementation of any foregoing embodiments It is the compound of formula (IIcc), wherein R in scheme3And R4It is hydrogen.It is in the another embodiment of any foregoing embodiments The compound of formula (IIcc), wherein R3For hydrogen or R4For methyl.It is formula in the another embodiment of any foregoing embodiments (IIcc) compound, wherein p are 1.Compound in the another embodiment of any foregoing embodiments for formula (IIcc), Wherein p is 2.Compound in the another embodiment of any foregoing embodiments for formula (IIcc), wherein p is 3.Any It is the compound of formula (IIcc) in the another embodiment of foregoing embodiments, wherein p is 4.In any foregoing embodiments It is the compound of formula (IIcc) in another embodiment, wherein p is 5.In the another embodiment of any foregoing embodiments For formula (IIcc) compound, wherein p is 6.Change in the another embodiment of any foregoing embodiments for formula (IIcc) Compound, wherein p are 7.Compound in the another embodiment of any foregoing embodiments for formula (IIcc), wherein p is 8. Compound in the another embodiment of any foregoing embodiments for formula (IIcc), wherein p is 9.
In another embodiment, this document describes the compound with formula (IId) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base, Huo Zhexiang R on adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IId), wherein R in some embodiments5For H.It is formula (IId) in some embodiments Compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IId), wherein R in some embodiments5For Unsubstituted alkyl.It is the compound of formula (IId), wherein R in some embodiments5For substituted alkyl.In some implementations It is the compound of formula (IId), wherein R in scheme5For substituted or unsubstituted aryl.It is formula (IId) in some embodiments Compound, wherein R5For substituted phenyl.It is the compound of formula (IId), wherein R in some embodiments5To be unsubstituted Phenyl.It is the compound of formula (IId), wherein R in some embodiments5For-CH3.It is formula (IId) in some embodiments Compound, wherein R5For-CH2CH3.It is the compound of formula (IId), wherein R in some embodiments5For-CH2CH2NH2。 It is the compound of formula (IId), wherein R in some embodiments5For-CH2CH2NH (alkyl).It is formula in some embodiments (IId) compound, wherein R5For-CH2CH2NH(CH3).It is formula in the another embodiment of any foregoing embodiments (IId) compound, wherein each R1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or it is substituted or unsubstituted Aryl.Compound in the another embodiment of any foregoing embodiments for formula (IId), wherein each R1And R2Each solely It is on the spot hydrogen, or substituted or unsubstituted alkyl.Change in the another embodiment of any foregoing embodiments for formula (IId) Compound, wherein each R1And R2It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IId), Wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In another implementation of any foregoing embodiments It is the compound of formula (IId), wherein two on adjacent carbon atom R in scheme1Or R2The carbon atom one that group is attached together with them Rise and form substituted or unsubstituted group of naphthene base.It is formula (IId) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group.Compound in the another embodiment of any foregoing embodiments for formula (IId), wherein on adjacent atom R1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl, wherein the heterocycle alkane Base group is substituted or unsubstituted pyrrolidine ring.It is formula (IId) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring.In the another of any foregoing embodiments It is the compound of formula (IId), the wherein R on adjacent atom in embodiment1And R5The atom shape that group is attached together with them Into substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperazine ring.It is in office It is the compound of formula (IId), wherein R in the another embodiment for foregoing embodiments of anticipating3And R4Hydrogen is each independently, or is taken Generation or unsubstituted alkyl.Compound in the another embodiment of any foregoing embodiments for formula (IId), wherein R3With R4It is each independently hydrogen or methyl.Compound in the another embodiment of any foregoing embodiments for formula (IId), its Middle R3And R4It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IId), wherein R3For hydrogen Or R4For methyl.Compound in the another embodiment of any foregoing embodiments for formula (IId), wherein p is 1.It is in office It is the compound of formula (IId) in the another embodiment for foregoing embodiments of anticipating, wherein p is 2.In any foregoing embodiments It is the compound of formula (IId) in another embodiment, wherein p is 3.It is in the another embodiment of any foregoing embodiments The compound of formula (IId), wherein p is 4.Compound in the another embodiment of any foregoing embodiments for formula (IId), Wherein p is 5.Compound in the another embodiment of any foregoing embodiments for formula (IId), wherein p is 6.Any It is the compound of formula (IId) in the another embodiment of foregoing embodiments, wherein p is 7.In the another of any foregoing embodiments It is the compound of formula (IId) in one embodiment, wherein p is 8.It is formula in the another embodiment of any foregoing embodiments (IId) compound, wherein p are 9.
In another embodiment, this document describes the compound with formula (IIdd) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and R1And R2It is each independently hydrogen, takes Generation or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or R1And R5Group is together with it The atom that is attached form substituted or unsubstituted heterocycloalkyl together；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIdd), wherein R in some embodiments5For H.It is formula in some embodiments (IIdd) compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IIdd) in some embodiments, Wherein R5For unsubstituted alkyl.It is the compound of formula (IIdd), wherein R in some embodiments5For substituted alkyl. It is the compound of formula (IIdd), wherein R in some embodiments5For substituted or unsubstituted aryl.In some embodiments For formula (IIdd) compound, wherein R5For substituted phenyl.It is the compound of formula (IIdd) in some embodiments, wherein R5For unsubstituted phenyl.It is the compound of formula (IIdd), wherein R in some embodiments5For-CH3.In some embodiment party It is the compound of formula (IIdd), wherein R in case5For-CH2CH3.It is the compound of formula (IIdd) in some embodiments, wherein R5For-CH2CH2NH2.It is the compound of formula (IIdd), wherein R in some embodiments5For-CH2CH2NH (alkyl).One It is the compound of formula (IIdd), wherein R in a little embodiments5For-CH2CH2NH(CH3).In the another of any foregoing embodiments It is the compound of formula (IIdd), wherein R in embodiment1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or is taken Generation or unsubstituted aryl.Compound in the another embodiment of any foregoing embodiments for formula (IIdd), wherein R1 And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is in the another embodiment of any foregoing embodiments The compound of formula (IIdd), wherein R1And R2For hydrogen.It is formula (IIdd) in the another embodiment of any foregoing embodiments Compound, wherein R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another of any foregoing embodiments It is the compound of formula (IIdd), the wherein R on adjacent atom in embodiment1And R5The atom that group is attached together with them Form substituted or unsubstituted heterocycloalkyl.It is formula (IIdd) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group, wherein the heterocycloalkyl is substituted or unsubstituted pyrrolidine ring.In the another of any foregoing embodiments It is the compound of formula (IIdd), the wherein R on adjacent atom in one embodiment1And R5The atom one that group is attached together with them Rise and form substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring. Compound in the another embodiment of any foregoing embodiments for formula (IIdd), the wherein R on adjacent atom1And R5Base The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is Substituted or unsubstituted piperazine ring.Compound in the another embodiment of any foregoing embodiments for formula (IIdd), its Middle R3And R4It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another embodiment of any foregoing embodiments For formula (IIdd) compound, wherein R3And R4It is each independently hydrogen or methyl.In another implementation of any foregoing embodiments It is the compound of formula (IIdd), wherein R in scheme3And R4It is hydrogen.It is in the another embodiment of any foregoing embodiments The compound of formula (IIdd), wherein R3For hydrogen or R4For methyl.It is formula in the another embodiment of any foregoing embodiments (IIdd) compound, wherein p are 1.Compound in the another embodiment of any foregoing embodiments for formula (IIdd), Wherein p is 2.Compound in the another embodiment of any foregoing embodiments for formula (IIdd), wherein p is 3.Any It is the compound of formula (IIdd) in the another embodiment of foregoing embodiments, wherein p is 4.In any foregoing embodiments It is the compound of formula (IIdd) in another embodiment, wherein p is 5.In the another embodiment of any foregoing embodiments For formula (IIdd) compound, wherein p is 6.Change in the another embodiment of any foregoing embodiments for formula (IIdd) Compound, wherein p are 7.Compound in the another embodiment of any foregoing embodiments for formula (IIdd), wherein p is 8. Compound in the another embodiment of any foregoing embodiments for formula (IIdd), wherein p is 9.
In another embodiment, this document describes the compound with formula (IIe) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base, Huo Zhexiang R on adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIe), wherein R in some embodiments5For H.It is formula (IIe) in some embodiments Compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IIe), wherein R in some embodiments5For Unsubstituted alkyl.It is the compound of formula (IIe), wherein R in some embodiments5For substituted alkyl.In some implementations It is the compound of formula (IIe), wherein R in scheme5For substituted or unsubstituted aryl.It is formula (IIe) in some embodiments Compound, wherein R5For substituted phenyl.It is the compound of formula (IIe), wherein R in some embodiments5To be unsubstituted Phenyl.It is the compound of formula (IIe), wherein R in some embodiments5For-CH3.It is formula (IIe) in some embodiments Compound, wherein R5For-CH2CH3.It is the compound of formula (IIe), wherein R in some embodiments5For-CH2CH2NH2。 It is the compound of formula (IIe), wherein R in some embodiments5For-CH2CH2NH (alkyl).It is formula in some embodiments (IIe) compound, wherein R5For-CH2CH2NH(CH3).It is formula in the another embodiment of any foregoing embodiments (IIe) compound, wherein each R1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or it is substituted or unsubstituted Aryl.Compound in the another embodiment of any foregoing embodiments for formula (IIe), wherein each R1And R2Each solely It is on the spot hydrogen, or substituted or unsubstituted alkyl.Change in the another embodiment of any foregoing embodiments for formula (IIe) Compound, wherein each R1And R2It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IIe), Wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In another implementation of any foregoing embodiments It is the compound of formula (IIe), wherein two on adjacent carbon atom R in scheme1Or R2The carbon atom one that group is attached together with them Rise and form substituted or unsubstituted group of naphthene base.It is formula (IIe) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group.Compound in the another embodiment of any foregoing embodiments for formula (IIa), wherein on adjacent atom R1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl, wherein the heterocycle alkane Base group is substituted or unsubstituted pyrrolidine ring.It is formula (IIe) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring.In the another of any foregoing embodiments It is the compound of formula (IIe), the wherein R on adjacent atom in embodiment1And R5The atom shape that group is attached together with them Into substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperazine ring.It is in office It is the compound of formula (IIe), wherein R in the another embodiment for foregoing embodiments of anticipating3And R4Hydrogen is each independently, or is taken Generation or unsubstituted alkyl.Compound in the another embodiment of any foregoing embodiments for formula (IIe), wherein R3With R4It is each independently hydrogen or methyl.Compound in the another embodiment of any foregoing embodiments for formula (IIe), its Middle R3And R4It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IIe), wherein R3For hydrogen Or R4For methyl.Compound in the another embodiment of any foregoing embodiments for formula (IIe), wherein p is 1.It is in office It is the compound of formula (IIe) in the another embodiment for foregoing embodiments of anticipating, wherein p is 2.In any foregoing embodiments It is the compound of formula (IIe) in another embodiment, wherein p is 3.It is in the another embodiment of any foregoing embodiments The compound of formula (IIe), wherein p is 4.Compound in the another embodiment of any foregoing embodiments for formula (IIe), Wherein p is 5.Compound in the another embodiment of any foregoing embodiments for formula (IIe), wherein p is 6.Any It is the compound of formula (IIe) in the another embodiment of foregoing embodiments, wherein p is 7.In the another of any foregoing embodiments It is the compound of formula (IIe) in one embodiment, wherein p is 8.It is formula in the another embodiment of any foregoing embodiments (IIe) compound, wherein p are 9.
In another embodiment, this document describes the compound with formula (IIee) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and R1And R2It is each independently hydrogen, takes Generation or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or R1And R5Group is together with it The atom that is attached form substituted or unsubstituted heterocycloalkyl together；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIee), wherein R in some embodiments5For H.It is formula in some embodiments (IIee) compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IIee) in some embodiments, Wherein R5For unsubstituted alkyl.It is the compound of formula (IIee), wherein R in some embodiments5For substituted alkyl. It is the compound of formula (IIee), wherein R in some embodiments5For substituted or unsubstituted aryl.In some embodiments For formula (IIee) compound, wherein R5For substituted phenyl.It is the compound of formula (IIee) in some embodiments, wherein R5For unsubstituted phenyl.It is the compound of formula (IIee), wherein R in some embodiments5For-CH3.In some embodiment party It is the compound of formula (IIee), wherein R in case5For-CH2CH3.It is the compound of formula (IIee) in some embodiments, wherein R5For-CH2CH2NH2.It is the compound of formula (IIee), wherein R in some embodiments5For-CH2CH2NH (alkyl).One It is the compound of formula (IIee), wherein R in a little embodiments5For-CH2CH2NH(CH3).In the another of any foregoing embodiments It is the compound of formula (IIee), wherein R in embodiment1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or is taken Generation or unsubstituted aryl.Compound in the another embodiment of any foregoing embodiments for formula (IIee), wherein R1 And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is in the another embodiment of any foregoing embodiments The compound of formula (IIee), wherein R1And R2For hydrogen.It is formula (IIee) in the another embodiment of any foregoing embodiments Compound, wherein R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another of any foregoing embodiments It is the compound of formula (IIee), the wherein R on adjacent atom in embodiment1And R5The atom that group is attached together with them Form substituted or unsubstituted heterocycloalkyl.It is formula (IIee) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group, wherein the heterocycloalkyl is substituted or unsubstituted pyrrolidine ring.In the another of any foregoing embodiments It is the compound of formula (IIee), the wherein R on adjacent atom in one embodiment1And R5The atom one that group is attached together with them Rise and form substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring. Compound in the another embodiment of any foregoing embodiments for formula (IIee), the wherein R on adjacent atom1And R5Base The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is Substituted or unsubstituted piperazine ring.Compound in the another embodiment of any foregoing embodiments for formula (IIee), its Middle R3And R4It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another embodiment of any foregoing embodiments For formula (IIee) compound, wherein R3And R4It is each independently hydrogen or methyl.In another implementation of any foregoing embodiments It is the compound of formula (IIee), wherein R in scheme3And R4It is hydrogen.It is in the another embodiment of any foregoing embodiments The compound of formula (IIee), wherein R3For hydrogen or R4For methyl.It is formula in the another embodiment of any foregoing embodiments (IIee) compound, wherein p are 1.Compound in the another embodiment of any foregoing embodiments for formula (IIee), Wherein p is 2.Compound in the another embodiment of any foregoing embodiments for formula (IIee), wherein p is 3.Any It is the compound of formula (IIee) in the another embodiment of foregoing embodiments, wherein p is 4.In any foregoing embodiments It is the compound of formula (IIee) in another embodiment, wherein p is 5.In the another embodiment of any foregoing embodiments For formula (IIee) compound, wherein p is 6.Change in the another embodiment of any foregoing embodiments for formula (IIee) Compound, wherein p are 7.Compound in the another embodiment of any foregoing embodiments for formula (IIee), wherein p is 8. Compound in the another embodiment of any foregoing embodiments for formula (IIee), wherein p is 9.
In another embodiment, this document describes the compound with formula (IIf) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base, Huo Zhexiang R on adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIf), wherein R in some embodiments5For H.It is formula (IIf) in some embodiments Compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IIf), wherein R in some embodiments5For Unsubstituted alkyl.It is the compound of formula (IIf), wherein R in some embodiments5For substituted alkyl.In some implementations It is the compound of formula (IIf), wherein R in scheme5For substituted or unsubstituted aryl.It is formula (IIf) in some embodiments Compound, wherein R5For substituted phenyl.It is the compound of formula (IIf), wherein R in some embodiments5To be unsubstituted Phenyl.It is the compound of formula (IIf), wherein R in some embodiments5For-CH3.It is formula (IIf) in some embodiments Compound, wherein R5For-CH2CH3.It is the compound of formula (IIf), wherein R in some embodiments5For-CH2CH2NH2。 It is the compound of formula (IIf), wherein R in some embodiments5For-CH2CH2NH (alkyl).It is formula in some embodiments (IIf) compound, wherein R5For-CH2CH2NH(CH3).It is formula in the another embodiment of any foregoing embodiments (IIf) compound, wherein each R1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or it is substituted or unsubstituted Aryl.Compound in the another embodiment of any foregoing embodiments for formula (IIf), wherein each R1And R2Each solely It is on the spot hydrogen, or substituted or unsubstituted alkyl.Change in the another embodiment of any foregoing embodiments for formula (IIf) Compound, wherein each R1And R2It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IIf), Wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In another implementation of any foregoing embodiments It is the compound of formula (IIf), wherein two on adjacent carbon atom R in scheme1Or R2The carbon atom one that group is attached together with them Rise and form substituted or unsubstituted group of naphthene base.It is formula (IIf) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group.Compound in the another embodiment of any foregoing embodiments for formula (IIf), wherein R3And R4Each solely It is on the spot hydrogen, or substituted or unsubstituted alkyl.Change in the another embodiment of any foregoing embodiments for formula (IIf) R on compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle alkane Base group, wherein the heterocycloalkyl is substituted or unsubstituted pyrrolidine ring.In the another of any foregoing embodiments It is the compound of formula (IIf), the wherein R on adjacent atom in embodiment1And R5The atom shape that group is attached together with them Into substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring.It is in office It is the compound of formula (IIf), the wherein R on adjacent atom in the another embodiment for foregoing embodiments of anticipating1And R5Group together with They be attached atom form substituted or unsubstituted heterocycloalkyl together, wherein the heterocycloalkyl for substitution or Unsubstituted piperazine ring.Compound in the another embodiment of any foregoing embodiments for formula (IIf), wherein R3And R4 It is each independently hydrogen or methyl.Compound in the another embodiment of any foregoing embodiments for formula (IIf), wherein R3And R4It is hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IIf), wherein R3For hydrogen or R4For methyl.Compound in the another embodiment of any foregoing embodiments for formula (IIf), wherein p is 1.Any It is the compound of formula (IIf) in the another embodiment of foregoing embodiments, wherein p is 2.In the another of any foregoing embodiments It is the compound of formula (IIf) in one embodiment, wherein p is 3.It is formula in the another embodiment of any foregoing embodiments (IIf) compound, wherein p are 4.Compound in the another embodiment of any foregoing embodiments for formula (IIf), its Middle p is 5.Compound in the another embodiment of any foregoing embodiments for formula (IIf), wherein p is 6.Before any The compound for formula (IIf) in the another embodiment of embodiment is stated, wherein p is 7.In the another of any foregoing embodiments It is the compound of formula (IIf) in embodiment, wherein p is 8.It is formula in the another embodiment of any foregoing embodiments (IIf) compound, wherein p are 9.
In another embodiment, this document describes the compound with formula (IIff) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and R1And R2It is each independently hydrogen, takes Generation or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or R1And R5Group is together with it The atom that is attached form substituted or unsubstituted heterocycloalkyl together；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIff), wherein R in some embodiments5For H.It is formula in some embodiments (IIff) compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IIff) in some embodiments, Wherein R5For unsubstituted alkyl.It is the compound of formula (IIff), wherein R in some embodiments5For substituted alkyl. It is the compound of formula (IIff), wherein R in some embodiments5For substituted or unsubstituted aryl.In some embodiments For formula (IIff) compound, wherein R5For substituted phenyl.It is the compound of formula (IIff) in some embodiments, wherein R5For unsubstituted phenyl.It is the compound of formula (IIff), wherein R in some embodiments5For-CH3.In some embodiment party It is the compound of formula (IIff), wherein R in case5For-CH2CH3.It is the compound of formula (IIff) in some embodiments, wherein R5For-CH2CH2NH2.It is the compound of formula (IIff), wherein R in some embodiments5For-CH2CH2NH (alkyl).One It is the compound of formula (IIff), wherein R in a little embodiments5For-CH2CH2NH(CH3).In the another of any foregoing embodiments It is the compound of formula (IIff), wherein R in embodiment1And R2Hydrogen, substituted or unsubstituted alkyl are each independently, or is taken Generation or unsubstituted aryl.Compound in the another embodiment of any foregoing embodiments for formula (IIff), wherein R1 And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is in the another embodiment of any foregoing embodiments The compound of formula (IIff), wherein R1And R2For hydrogen.It is formula (IIff) in the another embodiment of any foregoing embodiments Compound, wherein R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another of any foregoing embodiments It is the compound of formula (IIff), the wherein R on adjacent atom in embodiment1And R5The atom that group is attached together with them Form substituted or unsubstituted heterocycloalkyl.It is formula (IIff) in the another embodiment of any foregoing embodiments R in compound, wherein adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycle Alkyl group, wherein the heterocycloalkyl is substituted or unsubstituted pyrrolidine ring.In the another of any foregoing embodiments It is the compound of formula (IIff), the wherein R on adjacent atom in one embodiment1And R5The atom one that group is attached together with them Rise and form substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is substituted or unsubstituted piperidine ring. Compound in the another embodiment of any foregoing embodiments for formula (IIff), the wherein R on adjacent atom1And R5Base The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl, wherein the heterocycloalkyl is Substituted or unsubstituted piperazine ring.Compound in the another embodiment of any foregoing embodiments for formula (IIff), its Middle R3And R4It is each independently hydrogen, or substituted or unsubstituted alkyl.In the another embodiment of any foregoing embodiments For formula (IIff) compound, wherein R3And R4It is each independently hydrogen or methyl.In another implementation of any foregoing embodiments It is the compound of formula (IIff), wherein R in scheme3And R4It is hydrogen.It is in the another embodiment of any foregoing embodiments The compound of formula (IIff), wherein R3For hydrogen or R4For methyl.It is formula in the another embodiment of any foregoing embodiments (IIff) compound, wherein p are 1.Compound in the another embodiment of any foregoing embodiments for formula (IIff), Wherein p is 2.Compound in the another embodiment of any foregoing embodiments for formula (IIff), wherein p is 3.Any It is the compound of formula (IIff) in the another embodiment of foregoing embodiments, wherein p is 4.In any foregoing embodiments It is the compound of formula (IIff) in another embodiment, wherein p is 5.In the another embodiment of any foregoing embodiments For formula (IIff) compound, wherein p is 6.Change in the another embodiment of any foregoing embodiments for formula (IIff) Compound, wherein p are 7.Compound in the another embodiment of any foregoing embodiments for formula (IIff), wherein p is 8. Compound in the another embodiment of any foregoing embodiments for formula (IIff), wherein p is 9.
In another embodiment, this document describes the compound with formula (III) structure：
Wherein：
Y is phenols TRPV1 activators, and the hydrogen atom of wherein phenolic hydroxy group is bonded to-C (O)-C (R1)(R2)-(C(R1) (R2))n- Z covalent bond is replaced；
Z is-NR3R4Or-CO2H；
Each R1 and R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；And
N is 1 to 10 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (III) in some embodiments, wherein Y isR6Independently selected from Hydrogen, halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkane Base) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, Fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, Alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7To be substituted or unsubstituted Alkyl.It is the compound of formula (III) in some embodiments, wherein Y isR6Independently selected from hydrogen, halogen Element ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, Miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl are sub- Sulfone, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For unsubstituted alkyl or it is selected from The alkyl of one or more substituent groups of the following group：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkane Base ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, Aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.It is in some embodiments The compound of formula (III), wherein Y isR6For alkoxy；J is-NHC (O) R7Or-C (O) OR7；And R7 For unsubstituted alkyl or the alkyl for the one or more substituent groups for being selected from the following group：Halogen ,-CN ,-NH2、-NH(CH3)、-N (CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, fluothane oxygen Base, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and virtue Base sulfone.It is the compound of formula (III) in some embodiments, wherein Y isR6For alkoxy；J for- NHC(O)R7Or-C (O) OR7；And R7For unsubstituted alkyl.
It is the compound of formula (III) in some embodiments, wherein Y is
In some embodiment party It is the compound of formula (III) in case, wherein Y is
It is the compound of formula (III), wherein Y in some embodiments ForIt is the compound of formula (III) in some embodiments, wherein Y is
It is the compound of formula (III) in some embodiments, wherein Y isIt is the compound of formula (III) in some embodiments, wherein Y is
Compound in the another embodiment of any foregoing embodiments for formula (III), wherein each R1And R2Each It independently is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.In another reality of any foregoing embodiments The compound for formula (III) in scheme is applied, wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl. It is the compound of formula (III) in the another embodiment of any foregoing embodiments, wherein each R1And R2It is hydrogen.Any It is the compound of formula (III), wherein two on adjacent carbon atom R in the another embodiment of foregoing embodiments1Or R2Group The carbon atom being attached together with them forms substituted or unsubstituted group of naphthene base.In the another of any foregoing embodiments It is the compound of formula (III), wherein R in embodiment3And R4It is each independently hydrogen, or substituted or unsubstituted alkyl.It is in office It is the compound of formula (III), wherein R in the another embodiment for foregoing embodiments of anticipating3And R4It is each independently hydrogen or first Base.Compound in the another embodiment of any foregoing embodiments for formula (III), wherein R3And R4It is hydrogen.Any It is the compound of formula (III), wherein R in the another embodiment of foregoing embodiments3For hydrogen or R4For methyl.Any foregoing It is the compound of formula (III) in the another embodiment of embodiment, wherein n is 2.In another reality of any foregoing embodiments The compound for formula (III) in scheme is applied, wherein n is 3.It is formula in the another embodiment of any foregoing embodiments (III) compound, wherein n are 4.Compound in the another embodiment of any foregoing embodiments for formula (III), its Middle n is 5.Compound in the another embodiment of any foregoing embodiments for formula (III), wherein n is 6.Before any The compound for formula (III) in the another embodiment of embodiment is stated, wherein n is 7.In the another of any foregoing embodiments It is the compound of formula (III) in embodiment, wherein n is 8.It is formula in the another embodiment of any foregoing embodiments (III) compound, wherein n are 9.Compound in the another embodiment of any foregoing embodiments for formula (III), its Middle n is 10.
In another embodiment, this document describes the compound with formula (IIIa) structure：
Wherein：
Each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；And
P is 0 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIIa) in some embodiments, wherein each R1And R2Be each independently hydrogen, substitution or Unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIIa) in some embodiments, wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIa) in some embodiments, Wherein each R1And R2It is hydrogen.It is the compound of formula (IIIa) in some embodiments, wherein each R1And R2It is each independent Ground is hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIa), wherein adjacent carbon atom in some embodiments On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base.At some It is the compound of formula (IIIa) in embodiment, wherein p is 0.It is the compound of formula (IIIa) in some embodiments, wherein P is 1.It is the compound of formula (IIIa) in some embodiments, wherein p is 2.It is in some embodiments formula (IIIa) Compound, wherein p are 3.It is the compound of formula (IIIa) in some embodiments, wherein p is 4.In some embodiments For formula (IIIa) compound, wherein p is 5.It is the compound of formula (IIIa) in some embodiments, wherein p is 6.One It is the compound of formula (IIIa) in a little embodiments, wherein p is 7.It is the compound of formula (IIIa) in some embodiments, its Middle p is 8.It is the compound of formula (IIIa) in some embodiments, wherein p is 9.
In another embodiment, this document describes the compound with formula (IIIaa) structure：
Wherein：
Each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIIaa) in some embodiments, wherein each R1And R2It is each independently hydrogen, substitution Or unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIIaa) in some embodiments, wherein Each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the change of formula (IIIaa) in some embodiments Compound, wherein each R1And R2It is hydrogen.It is the compound of formula (IIIaa) in some embodiments, wherein each R1And R2Respectively From independently being hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIaa), wherein phase in some embodiments Two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted cycloalkyl base Group.Compound in the another embodiment of any foregoing embodiments for formula (IIIaa), wherein p is 1.Any foregoing It is the compound of formula (IIIaa) in the another embodiment of embodiment, wherein p is 2.In the another of any foregoing embodiments It is the compound of formula (IIIaa) in embodiment, wherein p is 3.It is formula in the another embodiment of any foregoing embodiments (IIIaa) compound, wherein p are 4.Chemical combination in the another embodiment of any foregoing embodiments for formula (IIIaa) Thing, wherein p are 5.Compound in the another embodiment of any foregoing embodiments for formula (IIIaa), wherein p is 6. It is the compound of formula (IIIaa) in the another embodiment of any foregoing embodiments, wherein p is 7.In any foregoing embodiment party It is the compound of formula (IIIaa) in the another embodiment of case, wherein p is 8.In another embodiment party of any foregoing embodiments It is the compound of formula (IIIaa) in case, wherein p is 9.
In another embodiment, this document describes the compound with formula (IIIb) structure：
Wherein：
Each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIIb) in some embodiments, wherein each R1And R2Be each independently hydrogen, substitution or Unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIIb) in some embodiments, wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIb) in some embodiments, Wherein each R1And R2It is hydrogen.It is the compound of formula (IIIb) in some embodiments, wherein each R1And R2It is each independent Ground is hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIb), wherein adjacent carbon atom in some embodiments On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base.At some It is the compound of formula (IIIb) in embodiment, wherein p is 0.It is the compound of formula (IIIb) in some embodiments, wherein P is 1.It is the compound of formula (IIIb) in some embodiments, wherein p is 2.It is in some embodiments formula (IIIb) Compound, wherein p are 3.It is the compound of formula (IIIb) in some embodiments, wherein p is 4.In some embodiments For formula (IIIb) compound, wherein p is 5.It is the compound of formula (IIIb) in some embodiments, wherein p is 6.One It is the compound of formula (IIIb) in a little embodiments, wherein p is 7.It is the compound of formula (IIIb) in some embodiments, its Middle p is 8.It is the compound of formula (IIIb) in some embodiments, wherein p is 9.
In another embodiment, this document describes the compound with formula (IIIbb) structure：
Wherein：
Each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIIbb) in some embodiments, wherein each R1And R2It is each independently hydrogen, substitution Or unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIIbb) in some embodiments, wherein Each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the change of formula (IIIbb) in some embodiments Compound, wherein each R1And R2It is hydrogen.It is the compound of formula (IIIbb) in some embodiments, wherein each R1And R2Respectively From independently being hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIbb), wherein phase in some embodiments Two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted cycloalkyl base Group.Compound in the another embodiment of any foregoing embodiments for formula (IIIbb), wherein p is 1.Any foregoing It is the compound of formula (IIIbb) in the another embodiment of embodiment, wherein p is 2.In the another of any foregoing embodiments It is the compound of formula (IIIbb) in embodiment, wherein p is 3.It is formula in the another embodiment of any foregoing embodiments (IIIbb) compound, wherein p are 4.Chemical combination in the another embodiment of any foregoing embodiments for formula (IIIbb) Thing, wherein p are 5.Compound in the another embodiment of any foregoing embodiments for formula (IIIbb), wherein p is 6. It is the compound of formula (IIIbb) in the another embodiment of any foregoing embodiments, wherein p is 7.In any foregoing embodiment party It is the compound of formula (IIIbb) in the another embodiment of case, wherein p is 8.In another embodiment party of any foregoing embodiments It is the compound of formula (IIIbb) in case, wherein p is 9.
In another embodiment, this document describes the compound with formula (IIIc) structure：
Wherein：
Each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；And
P is 0 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIIc) in some embodiments, wherein each R1And R2Be each independently hydrogen, substitution or Unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIIc) in some embodiments, wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIc) in some embodiments, Wherein each R1And R2It is hydrogen.It is the compound of formula (IIIc) in some embodiments, wherein each R1And R2It is each independent Ground is hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIc), wherein adjacent carbon atom in some embodiments On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base.At some It is the compound of formula (IIIc) in embodiment, wherein p is 0.It is the compound of formula (IIIc) in some embodiments, wherein P is 1.It is the compound of formula (IIIc) in some embodiments, wherein p is 2.It is in some embodiments formula (IIIc) Compound, wherein p are 3.It is the compound of formula (IIIc) in some embodiments, wherein p is 4.In some embodiments For formula (IIIc) compound, wherein p is 5.It is the compound of formula (IIIc) in some embodiments, wherein p is 6.One It is the compound of formula (IIIc) in a little embodiments, wherein p is 7.It is the compound of formula (IIIc) in some embodiments, its Middle p is 8.It is the compound of formula (IIIc) in some embodiments, wherein p is 9.
In another embodiment, this document describes the compound with formula (IIIcc) structure：
Wherein：
Each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIIcc) in some embodiments, wherein each R1And R2It is each independently hydrogen, substitution Or unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIIcc) in some embodiments, wherein Each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the change of formula (IIIcc) in some embodiments Compound, wherein each R1And R2It is hydrogen.It is the compound of formula (IIIcc) in some embodiments, wherein each R1And R2Respectively From independently being hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIcc), wherein phase in some embodiments Two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted cycloalkyl base Group.Compound in the another embodiment of any foregoing embodiments for formula (IIIcc), wherein p is 1.Any foregoing It is the compound of formula (IIIcc) in the another embodiment of embodiment, wherein p is 2.In the another of any foregoing embodiments It is the compound of formula (IIIcc) in embodiment, wherein p is 3.It is formula in the another embodiment of any foregoing embodiments (IIIcc) compound, wherein p are 4.Chemical combination in the another embodiment of any foregoing embodiments for formula (IIIcc) Thing, wherein p are 5.Compound in the another embodiment of any foregoing embodiments for formula (IIIcc), wherein p is 6. It is the compound of formula (IIIcc) in the another embodiment of any foregoing embodiments, wherein p is 7.In any foregoing embodiment party It is the compound of formula (IIIcc) in the another embodiment of case, wherein p is 8.In another embodiment party of any foregoing embodiments It is the compound of formula (IIIcc) in case, wherein p is 9.
In another embodiment, this document describes the compound with formula (IIId) structure：
Wherein：
Each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；And
P is 0 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIId) in some embodiments, wherein each R1And R2Be each independently hydrogen, substitution or Unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIId) in some embodiments, wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIId) in some embodiments, Wherein each R1And R2It is hydrogen.It is the compound of formula (IIId) in some embodiments, wherein each R1And R2It is each independent Ground is hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIId), wherein adjacent carbon atom in some embodiments On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base.At some It is the compound of formula (IIId) in embodiment, wherein p is 0.It is the compound of formula (IIId) in some embodiments, wherein P is 1.It is the compound of formula (IIId) in some embodiments, wherein p is 2.It is in some embodiments formula (IIId) Compound, wherein p are 3.It is the compound of formula (IIId) in some embodiments, wherein p is 4.In some embodiments For formula (IIId) compound, wherein p is 5.It is the compound of formula (IIId) in some embodiments, wherein p is 6.One It is the compound of formula (IIId) in a little embodiments, wherein p is 7.It is the compound of formula (IIId) in some embodiments, its Middle p is 8.It is the compound of formula (IIId) in some embodiments, wherein p is 9.
In another embodiment, this document describes the compound with formula (IIIdd) structure：
Wherein：
Each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIIdd) in some embodiments, wherein each R1And R2It is each independently hydrogen, substitution Or unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIIdd) in some embodiments, wherein Each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the change of formula (IIIdd) in some embodiments Compound, wherein each R1And R2It is hydrogen.It is the compound of formula (IIIdd) in some embodiments, wherein each R1And R2Respectively From independently being hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIdd), wherein phase in some embodiments Two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted cycloalkyl base Group.Compound in the another embodiment of any foregoing embodiments for formula (IIIdd), wherein p is 1.Any foregoing It is the compound of formula (IIIdd) in the another embodiment of embodiment, wherein p is 2.In the another of any foregoing embodiments It is the compound of formula (IIIdd) in embodiment, wherein p is 3.It is formula in the another embodiment of any foregoing embodiments (IIIdd) compound, wherein p are 4.Chemical combination in the another embodiment of any foregoing embodiments for formula (IIIdd) Thing, wherein p are 5.Compound in the another embodiment of any foregoing embodiments for formula (IIIdd), wherein p is 6. It is the compound of formula (IIIdd) in the another embodiment of any foregoing embodiments, wherein p is 7.In any foregoing embodiment party It is the compound of formula (IIIdd) in the another embodiment of case, wherein p is 8.In another embodiment party of any foregoing embodiments It is the compound of formula (IIIdd) in case, wherein p is 9.
In another embodiment, this document describes the compound with formula (IIIe) structure：
Wherein：
Each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；And
P is 0 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIIe) in some embodiments, wherein each R1And R2Be each independently hydrogen, substitution or Unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIIe) in some embodiments, wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIe) in some embodiments, Wherein each R1And R2It is hydrogen.It is the compound of formula (IIIe) in some embodiments, wherein each R1And R2It is each independent Ground is hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIe), wherein adjacent carbon atom in some embodiments On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base.At some It is the compound of formula (IIIe) in embodiment, wherein p is 0.It is the compound of formula (IIIe) in some embodiments, wherein P is 1.It is the compound of formula (IIIe) in some embodiments, wherein p is 2.It is in some embodiments formula (IIIe) Compound, wherein p are 3.It is the compound of formula (IIIe) in some embodiments, wherein p is 4.In some embodiments For formula (IIIe) compound, wherein p is 5.It is the compound of formula (IIIe) in some embodiments, wherein p is 6.One It is the compound of formula (IIIe) in a little embodiments, wherein p is 7.It is the compound of formula (IIIe) in some embodiments, its Middle p is 8.It is the compound of formula (IIIe) in some embodiments, wherein p is 9.
In another embodiment, this document describes the compound with formula (IIIee) structure：
Wherein：
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIIee) in some embodiments, wherein each R1And R2It is each independently hydrogen, substitution Or unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIIee) in some embodiments, wherein Each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the change of formula (IIIee) in some embodiments Compound, wherein each R1And R2It is hydrogen.It is the compound of formula (IIIee) in some embodiments, wherein each R1And R2Respectively From independently being hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIee), wherein phase in some embodiments Two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted cycloalkyl base Group.Compound in the another embodiment of any foregoing embodiments for formula (IIIee), wherein p is 1.Any foregoing It is the compound of formula (IIIee) in the another embodiment of embodiment, wherein p is 2.In the another of any foregoing embodiments It is the compound of formula (IIIee) in embodiment, wherein p is 3.It is formula in the another embodiment of any foregoing embodiments (IIIee) compound, wherein p are 4.Chemical combination in the another embodiment of any foregoing embodiments for formula (IIIee) Thing, wherein p are 5.Compound in the another embodiment of any foregoing embodiments for formula (IIIee), wherein p is 6. It is the compound of formula (IIIee) in the another embodiment of any foregoing embodiments, wherein p is 7.In any foregoing embodiment party It is the compound of formula (IIIee) in the another embodiment of case, wherein p is 8.In another embodiment party of any foregoing embodiments It is the compound of formula (IIIee) in case, wherein p is 9.
In another embodiment, this document describes the compound with formula (IIIf) structure：
Wherein：
Each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；And
P is 0 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIIf) in some embodiments, wherein each R1And R2Be each independently hydrogen, substitution or Unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIIf) in some embodiments, wherein each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIf) in some embodiments, Wherein each R1And R2It is hydrogen.It is the compound of formula (IIIf) in some embodiments, wherein each R1And R2It is each independent Ground is hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIf), wherein adjacent carbon atom in some embodiments On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base.At some It is the compound of formula (IIIf) in embodiment, wherein p is 0.It is the compound of formula (IIIf) in some embodiments, wherein P is 1.It is the compound of formula (IIIf) in some embodiments, wherein p is 2.It is in some embodiments formula (IIIf) Compound, wherein p are 3.It is the compound of formula (IIIf) in some embodiments, wherein p is 4.In some embodiments For formula (IIIf) compound, wherein p is 5.It is the compound of formula (IIIf) in some embodiments, wherein p is 6.One It is the compound of formula (IIIf) in a little embodiments, wherein p is 7.It is the compound of formula (IIIf) in some embodiments, its Middle p is 8.It is the compound of formula (IIIf) in some embodiments, wherein p is 9.
In another embodiment, this document describes the compound with formula (IIIff) structure：
Wherein：
Each R1And R2It is each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substitution or not Substituted acyl group, or two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them formed substitution or Unsubstituted group of naphthene base；And
P is 1 to 9 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IIIff) in some embodiments, wherein each R1And R2It is each independently hydrogen, substitution Or unsubstituted alkyl, or substituted or unsubstituted aryl.It is the compound of formula (IIIff) in some embodiments, wherein Each R1And R2It is each independently hydrogen, or substituted or unsubstituted alkyl.It is the change of formula (IIIff) in some embodiments Compound, wherein each R1And R2It is hydrogen.It is the compound of formula (IIIff) in some embodiments, wherein each R1And R2Respectively From independently being hydrogen, or substituted or unsubstituted alkyl.It is the compound of formula (IIIff), wherein phase in some embodiments Two R on adjacent carbon atom1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted cycloalkyl base Group.Compound in the another embodiment of any foregoing embodiments for formula (IIIff), wherein p is 1.Any foregoing It is the compound of formula (IIIff) in the another embodiment of embodiment, wherein p is 2.In the another of any foregoing embodiments It is the compound of formula (IIIff) in embodiment, wherein p is 3.It is formula in the another embodiment of any foregoing embodiments (IIIff) compound, wherein p are 4.Chemical combination in the another embodiment of any foregoing embodiments for formula (IIIff) Thing, wherein p are 5.Compound in the another embodiment of any foregoing embodiments for formula (IIIff), wherein p is 6. It is the compound of formula (IIIff) in the another embodiment of any foregoing embodiments, wherein p is 7.In any foregoing embodiment party It is the compound of formula (IIIff) in the another embodiment of case, wherein p is 8.In another embodiment party of any foregoing embodiments It is the compound of formula (IIIff) in case, wherein p is 9.
In another embodiment, this document describes the compound with formula (IV) structure：
Wherein：
Y is phenols TRPV1 activators, and the hydrogen atom of wherein phenolic hydroxy group is bonded toBe total to Valence link is replaced；
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；
Each R1It independently is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group；
R2For hydrogen, or substituted or unsubstituted alkyl；And
N is 0 to 4 integer；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (IV) in some embodiments, wherein Y isR6Independently selected from hydrogen, Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,- C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluothane Base, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl Sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For substituted or unsubstituted alkane Base.It is the compound of formula (IV) in some embodiments, wherein Y isR6Independently selected from hydrogen, halogen Element ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, Miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl are sub- Sulfone, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For unsubstituted alkyl or it is selected from The alkyl of one or more substituent groups of the following group：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkane Base ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, Aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.It is in some embodiments The compound of formula (IV), wherein Y isR6For alkoxy；J is-NHC (O) R7Or-C (O) OR7；And R7For Unsubstituted alkyl or be selected from the following group one or more substituent groups alkyl：Halogen ,-CN ,-NH2、-NH(CH3)、-N (CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, fluothane oxygen Base, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and virtue Base sulfone.It is the compound of formula (IV) in some embodiments, wherein Y isR6For alkoxy；J is-NHC (O)R7Or-C (O) OR7；And R7For unsubstituted alkyl.
It is the compound of formula (IV) in some embodiments, wherein Y is
In some embodiment party It is the compound of formula (IV) in case, wherein Y is
It is the compound of formula (IV) in some embodiments, wherein Y isIt is the compound of formula (IV) in some embodiments, wherein Y is
It is the compound of formula (IV) in some embodiments, wherein Y isIt is the compound of formula (IV) in some embodiments, wherein Y is
It is the compound of formula (IV), wherein R in some embodiments5For H.It is in some embodiments formula (IV) Compound, wherein R5For substituted or unsubstituted alkyl.It is the compound of formula (IV), wherein R in some embodiments5For not Substituted alkyl.It is the compound of formula (IV), wherein R in some embodiments5For substituted alkyl.In some embodiments In be formula (IV) compound, wherein R5For substituted or unsubstituted aryl.It is the chemical combination of formula (IV) in some embodiments Thing, wherein R5For substituted phenyl.It is the compound of formula (IV), wherein R in some embodiments5For unsubstituted phenyl. It is the compound of formula (IV), wherein R in some embodiments5For-CH3.It is the compound of formula (IV) in some embodiments, Wherein R5For-CH2CH3.It is the compound of formula (IV), wherein R in some embodiments5For-CH2CH2NH2.In some implementations It is the compound of formula (IV), wherein R in scheme5For-CH2CH2NH (alkyl).It is the chemical combination of formula (IV) in some embodiments Thing, wherein R5For-CH2CH2NH(CH3).It is the compound of formula (IV) in some embodiments, wherein n is 1 and R1For substitution Or unsubstituted alkyl.It is the compound of formula (IV) in some embodiments, wherein n is 1 and R1For unsubstituted alkyl. It is the compound of formula (IV) in some embodiments, wherein n is 0.In the another embodiment of any foregoing embodiments For formula (IV) compound, wherein R2For hydrogen.Chemical combination in the another embodiment of any foregoing embodiments for formula (IV) Thing, wherein R2For substituted or unsubstituted alkyl.
Compound in the another embodiment of any foregoing embodiments for formula (IV), wherein n is 0, R2For hydrogen simultaneously And R5For hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (IV), wherein n is 0, R2For hydrogen simultaneously And R5For methyl.
On the other hand, this document describes the compound with formula (V) structure：
Wherein：
Y is phenols TRPV1 activators, and the hydrogen atom of wherein phenolic hydroxy group is bonded to-C (O)-X- (C (R1)(R2))n- Z's Covalent bond is replaced；
X is-C (R1)(R2)-、-O-、-N(R5)-or-S-；
N is 1 to 10 integer；
Z is-NR3R4Or-CO2H；
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or R1And R2Together with it The carbon atom that is attached form substituted or unsubstituted group of naphthene base, or two R on adjacent carbon atom together1Or R2Group The carbon atom being attached together with them forms substituted or unsubstituted group of naphthene base, or the R on adjacent atom1And R5Base The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl；And
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (V) in some embodiments, wherein Z is-NR3R4.It is formula (V) in other embodiments Compound, wherein Z be-CO2H。
It is the compound of formula (V) in some embodiments, wherein Y isR6Independently selected from hydrogen, Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,- C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluothane Base, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl Sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For substituted or unsubstituted alkane Base.It is the compound of formula (V) in some embodiments, wherein Y isR6Independently selected from hydrogen, halogen ,- CN、-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkane Base, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, virtue Base sulfoxide, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For unsubstituted alkyl or it is selected from the following group One or more substituent groups alkyl：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,- C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, fragrant oxygen Base, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.It is formula (V) in some embodiments Compound, wherein Y isR6For alkoxy；J is-NHC (O) R7Or-C (O) OR7；And R7To be unsubstituted Alkyl or be selected from the following group one or more substituent groups alkyl：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、- OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (= O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, heterocycle alkane Base, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.One It is the compound of formula (V) in a little embodiments, wherein Y isR6For alkoxy；J is-NHC (O) R7Or-C (O)OR7；And R7For unsubstituted alkyl.
It is the compound of formula (V) in some embodiments, wherein Y is
In some embodiment party It is the compound of formula (V) in case, wherein Y isIn some embodiments For formula (V) compound, wherein Y is
It is the compound of formula (V) in some embodiments, wherein Y is
It is the compound of formula (V) in some embodiments, wherein Y isIt is the compound of formula (V) in some embodiments, wherein Y is
It is the compound of formula (V) in some embodiments, wherein X is-O-.It is in some embodiments formula (V) Compound, wherein X are-S-.It is the compound of formula (V) in some embodiments, wherein X is-C (R1)(R2)-.In some realities The compound for formula (V) in scheme is applied, wherein X is-C (R1)(R2)-and R1And R2It is each independently hydrogen, substitution or does not take The alkyl in generation, or substituted or unsubstituted aryl.It is the compound of formula (V) in some embodiments, wherein X is-CH2-. It is the compound of formula (V) in some embodiments, wherein X is-CH (CH3)-.It is the chemical combination of formula (V) in some embodiments Thing, wherein X are-C (CH3)2-.It is the compound of formula (V) in some embodiments, wherein X is-C (R1)(R2)-, and R1With R2The carbon atom being attached together with them forms substituted or unsubstituted group of naphthene base.It is formula in some embodiments (V) compound, wherein X are-N (R5)-.It is the compound of formula (V) in some embodiments, wherein X is-N (R5)-and R5For substituted or unsubstituted alkyl.It is the compound of formula (V) in some embodiments, wherein X is-N (R5)-and R5For Unsubstituted alkyl.It is the compound of formula (V) in some embodiments, wherein X is-N (R5)-and R5For substituted alkyl. It is the compound of formula (V) in some embodiments, wherein X is-N (R5)-and R5For substituted or unsubstituted aryl.One It is the compound of formula (V) in a little embodiments, wherein X is-N (R5)-and R5For substituted phenyl.In some embodiments For formula (V) compound, wherein X is-N (R5)-and R5For unsubstituted phenyl.It is the change of formula (V) in some embodiments Compound, wherein X are-NH-.It is the compound of formula (V) in some embodiments, wherein X is-N (CH3)-.In some embodiment party It is the compound of formula (V) in case, wherein X is-N (CH2CH3)-.It is the compound of formula (V), wherein X in some embodiments For-N (CH2CH2NH2)-.It is the compound of formula (V) in some embodiments, wherein X is-N (CH2CH2NH (alkyl))-. It is the compound of formula (V) in some embodiments, wherein X is-N (CH2CH2NH(CH3))-.In entering for any foregoing embodiments It is the compound of formula (V) in one step embodiment, wherein Z is-CO2H.In the another embodiment of any foregoing embodiments For formula (V) compound, wherein Z is-NR3R4.Chemical combination in the another embodiment of any foregoing embodiments for formula (V) Thing, wherein Z are-NR3R4And R3And R4It is each independently hydrogen, or substituted or unsubstituted alkyl.In any foregoing embodiment party It is the compound of formula (V) in the another embodiment of case, wherein Z is-NR3R4And R3And R4It is each independently hydrogen or methyl. Compound in the another embodiment of any foregoing embodiments for formula (V), wherein Z is-NR3R4And R3And R4It is Hydrogen.Compound in the another embodiment of any foregoing embodiments for formula (V), wherein Z is-NR3R4And R3For hydrogen or R4For methyl.Compound in the another embodiment of any foregoing embodiments for formula (V), wherein n is 1.Before any The compound for formula (V) in the another embodiment of embodiment is stated, wherein n is 2.In another reality of any foregoing embodiments The compound for formula (V) in scheme is applied, wherein n is 3.It is formula (V) in the another embodiment of any foregoing embodiments Compound, wherein n are 4.Compound in the another embodiment of any foregoing embodiments for formula (V), wherein n is 5. It is the compound of formula (V) in the another embodiment of any foregoing embodiments, wherein n is 6.In any foregoing embodiments It is the compound of formula (V) in another embodiment, wherein n is 7.It is formula in the another embodiment of any foregoing embodiments (V) compound, wherein n are 8.Compound in the another embodiment of any foregoing embodiments for formula (V), wherein n For 9.Compound in the another embodiment of any foregoing embodiments for formula (V), wherein n is 10.
On the other hand, this document describes the compound with formula (VI) structure：
Wherein：
Y is phenols TRPV1 activators, and the hydrogen atom of wherein phenolic hydroxy group is bonded to-C (O)-X- (C (R1)(R2))n- Z's Covalent bond is replaced；
X is-C (R1)(R2)-、-O-、-N(R5)-or-S-；
N is 1 to 10 integer；
Z is-NR3R4；
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or R1And R2Together with it The carbon atom that is attached form substituted group of naphthene base, or R together1And R2The carbon atom being attached together with them is formed not Two R in substituted cyclopropyl, cyclobutyl, cyclopenta, suberyl or cyclooctyl, or adjacent carbon atom1Or R2Group is together with it The carbon atom that is attached form substituted or unsubstituted group of naphthene base, or the R on adjacent atom together1And R5Group is together with it The atom that is attached form substituted or unsubstituted heterocycloalkyl together；And
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；Or
Its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is the compound of formula (VI) in some embodiments, wherein Y is
In some embodiment party It is the compound of formula (VI) in case, wherein Y is
It is the compound of formula (VI) in some embodiments, wherein Y isIt is the compound of formula (VI) in some embodiments, wherein Y is
It is the compound of formula (VI) in some embodiments, wherein Y isIt is the compound of formula (VI) in some embodiments, wherein Y is
It is the compound of formula (VI) in some embodiments, wherein X is-O-.It is formula (VI) in some embodiments Compound, wherein X be-S-.It is the compound of formula (VI) in some embodiments, wherein X is-C (R1)(R2)-.At some It is the compound of formula (VI) in embodiment, wherein X is-C (R1)(R2)-and R1And R2Be each independently hydrogen, substitution or not Substituted alkyl, or substituted or unsubstituted aryl.In some embodiments be formula (VI) compound, wherein X for- CH2-.It is the compound of formula (VI) in some embodiments, wherein X is-CH (CH3)-.It is formula in some embodiments (VI) compound, wherein X are-C (CH3)2-.It is the compound of formula (VI) in some embodiments, wherein X is-C (R1) (R2)-, and R1And R2The carbon atom being attached together with them forms substituted group of naphthene base.In some embodiments For formula (VI) compound, wherein X is-C (R1)(R2)-, and R1And R2The carbon atom being attached together with them is formed and not taken The cyclopropyl group in generation.It is the compound of formula (VI) in some embodiments, wherein X is-C (R1)(R2)-, and R1And R2 The carbon atom being attached together with them forms unsubstituted cyclobutyl group.It is the chemical combination of formula (VI) in some embodiments Thing, wherein X are-C (R1)(R2)-, and R1And R2The carbon atom being attached together with them forms unsubstituted cyclopenta base Group.It is the compound of formula (VI) in some embodiments, wherein X is-C (R1)(R2)-, and R1And R2It is attached together with them Carbon atom form unsubstituted cycloheptyl radicals together.It is the compound of formula (VI) in some embodiments, wherein X is-C (R1)(R2)-, and R1And R2The carbon atom being attached together with them forms unsubstituted cyclooctyl group.In some implementations It is the compound of formula (VI) in scheme, wherein X is-N (R5)-.It is the compound of formula (VI), wherein X in some embodiments For-N (R5)-and R5For substituted or unsubstituted alkyl.It is the compound of formula (VI) in some embodiments, wherein X is-N (R5)-and R5For unsubstituted alkyl.It is the compound of formula (VI) in some embodiments, wherein X is-N (R5)-and R5For substituted alkyl.It is the compound of formula (VI) in some embodiments, wherein X is-N (R5)-and R5For substitution or not Substituted aryl.It is the compound of formula (VI) in some embodiments, wherein X is-N (R5)-and R5For substituted phenyl. It is the compound of formula (VI) in some embodiments, wherein X is-N (R5)-and R5For unsubstituted phenyl.In some implementations It is the compound of formula (VI) in scheme, wherein X is-NH-.It is the compound of formula (VI) in some embodiments, wherein X is-N (CH3)-.It is the compound of formula (VI) in some embodiments, wherein X is-N (CH2CH3)-.It is in some embodiments The compound of formula (VI), wherein X is-N (CH2CH2NH2)-.In some embodiments be formula (VI) compound, wherein X for- N(CH2CH2NH (alkyl))-.It is the compound of formula (VI) in some embodiments, wherein X is-N (CH2CH2NH(CH3))-。 Compound in the another embodiment of any foregoing embodiments for formula (VI), wherein Z is-NR3R4And R3And R4Each It independently is hydrogen, or substituted or unsubstituted alkyl.It is formula (VI) in the another embodiment of any foregoing embodiments Compound, wherein Z are-NR3R4And R3And R4It is each independently hydrogen or methyl.In another reality of any foregoing embodiments The compound for formula (VI) in scheme is applied, wherein Z is-NR3R4And R3And R4It is hydrogen.In the another of any foregoing embodiments It is the compound of formula (VI) in one embodiment, wherein Z is-NR3R4And R3For hydrogen or R4For methyl.In any foregoing implementation It is the compound of formula (VI) in the another embodiment of scheme, wherein n is 1.In another embodiment party of any foregoing embodiments It is the compound of formula (VI) in case, wherein n is 2.Change in the another embodiment of any foregoing embodiments for formula (VI) Compound, wherein n are 3.Compound in the another embodiment of any foregoing embodiments for formula (VI), wherein n is 4. It is the compound of formula (VI) in the another embodiment of any foregoing embodiments, wherein n is 5.In any foregoing embodiments Another embodiment in be formula (VI) compound, wherein n be 6.In the another embodiment of any foregoing embodiments For formula (VI) compound, wherein n is 7.Compound in the another embodiment of any foregoing embodiments for formula (VI), Wherein n is 8.Compound in the another embodiment of any foregoing embodiments for formula (VI), wherein n is 9.Before any The compound for formula (VI) in the another embodiment of embodiment is stated, wherein n is 10.
It is selected from following compound in another embodiment：
Or it is its pharmaceutically acceptable salt, pharmaceutically acceptable Solvate, or hydrate.
It is selected from following compound in another embodiment：
Or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
It is in another embodiment the compound with following structure, or its pharmaceutically acceptable salt, pharmaceutically may be used The solvate of receiving, or hydrate：
The synthesis of compound
In some embodiments, using the means described in Chemistry Literature, using method described herein, or it is passed through Combine to realize the synthesis of compound described herein.In addition, solvent as shown herein, temperature and other reaction conditions can become Change.
In other embodiments, the initial substance and reagent for synthesizing compound described herein are synthesis or from all As but be not limited to Sigma-Aldrich Corp., Fisher Scientific (Fisher Chemicals) and Acros Organics commercial source is obtained.
In further embodiment, compound as described herein and other related compounds with different substituents Synthesized using the techniques described herein and material and technology recognized in the art and material, such as Fieser and Fieser ' s Reagents for Organic Synthesis, 1-17 volumes (John Wiley and Sons, 1991)； Rodd ' s Chemistry of Carbon Compounds, 1-5 volumes and supplementary issue (Elsevier Science Publishers, 1989)；Organic Reactions, 1-40 volumes (John Wiley and Sons, 1991), Larock ' s Comprehensive Organic Transformations(VCH Publishers Inc.,1989),March, Advanced Organic Chemistry fourth editions, (Wiley 1992)；Carey and Sundberg, Advanced Organic Chemistry fourth editions, A volumes and B volumes (Plenum 2000,2001) and Green and Wuts, Protective The Groups in Organic Synthesis third editions, (disclosure, institute because as described in (Wiley 1999) There are these to be all incorporated by reference into this).Reaction can be derived from for preparing the conventional method of compound as disclosed herein, and And can be by using suitable reagent and condition, for example, being introduced into formula as provided herein a variety of parts for finding to improve this Reaction.
In some embodiments, as following scheme briefly prepares compound as described herein.
Scheme 1
In some embodiments, as following scheme briefly prepares compound as described herein.
Scheme 2
The other forms of compound
In some cases, compound as described herein can be with diastereoisomer, enantiomter or other solids Isomeric forms are present.Provided herein is compound including all diastereo-isomerisms, enantiomerism and epimerism form with And its appropriate mixture.Can by chromatography, by formed diastereoisomer and via recrystallization or chromatography or It is combined separation to carry out the separation of stereoisomer.(Jean Jacques,Andre Collet,Samuel H.Wilen,“Enantiomers,Racemates and Resolutions”,John Wiley And Sons,Inc., 1981, be incorporated by reference into because of the disclosure in this).Stereoisomer can also be obtained by stereoselective syntheses.
In some cases, compound can exist with dynamic isomer.All dynamic isomers are all included in herein In described formula.
Method described herein and composition include making for amorphous form and crystal form (also referred to as polymorph) With.Compound as described herein can be the form of pharmaceutically acceptable salt.Equally, these chemical combination with same type activity The active metabolite of thing is also included in that scope of the present disclosure interior.In addition, compound as described herein can be with non-solvent Change form and solvation form exist together with pharmaceutically acceptable solvent such as water, ethanol.It is additionally considered that as shown herein The solvation form of compound is disclosed herein.
Formula (I) as described herein, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、 (IIIcc), the compound of (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) Or the prodrug that its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate are TRPV1 activators." prodrug " Refer to the medicament for being converted into parent drug in vivo.Formula (I) as described herein, (II), (IIa), (IIaa), (IIb), (IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、 (IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、 (IIIff), (IV), (V) or (VI) compound, or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or Hydrate is related to the new type water-solubility prodrug and its synthesis and application method of TRPV1 activators.Except the compound especially identified Outside, these derivatives being capable of the Viability parent compound of electronation when exposed to physiological conditions.These derivative ratios Its parent drug has significantly higher hydrophily/water solubility, therefore can more be impregnated in conventional aqueous formulation.Herein further Describe and modify the chemical constitution of parent molecule to improve capsaicine, its analog and other TRPV1 by using hydrophilic parts The water miscible method of activator.In some embodiments as described herein, the alkali that can be protonated in acid condition The introducing of property part improves the solubility of TRPV1 prodrugs.In some embodiments as described herein, by increasing capacitance it is possible to increase overall parent The introducing of the acidic moiety of aqueous feature improves the solubility of TRPV1 prodrugs.Devise prodrug as described herein so that in mother The structural derivative of body medicine is delivered to body and/or after specific physiological conditions, and the parent drug is with bright The fixed speed release of fidelity.
Can be by compound isotope marks as described herein (for example, with radio isotope) or by other means mark Note, includes but is not limited to, using chromophore or fluorescing fractions, bioluminescence label, can photoactivation label or chemiluminescence label.
Compound as described herein includes the compound of isotope marks, and the compound of the isotope marks is with being documented in this Multiple formulas shown in text are identical with those in structure, but in fact one or more atoms by with the original found with Chang Tianran The atom of protonatomic mass or the different atomic mass of mass number or mass number is replaced.Isotope in shown compound can be mixed Example includes the isotope of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as, for example, being respectively2H、3H、13C、14C、15N、18O、17O、35S 、18F、36Cl.The compound of some isotope marks as described herein, for example, being wherein mixed with radio isotope such as3H and14C Those be useful in medicine and/or substrate tissue measure of spread.In addition, with isotope such as deuterium (i.e.2H substitution) can be carried For some treatment advantages caused by higher metabolic stability, such as, for example, the Half-life in vivo or the dosage of attenuating that increase It is required that.
Compound as described herein can be made and/or be used as pharmaceutically acceptable salt.Pharmaceutically may be used The type of the salt of receiving includes but is not limited to：(1) by the free alkali form of compound with it is following pharmaceutically acceptable inorganic Acid-addition salts formed by acid or organic acid reaction, the inorganic acid, such as, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, inclined phosphorus Acid etc.；The organic acid, such as, acetic acid, propionic acid, caproic acid, pentamethylene propionic acid, glycolic, pyruvic acid, lactic acid, malonic acid, Butanedioic acid, malic acid, maleic acid, fumaric acid, trifluoroacetic acid, tartaric acid, citric acid, benzoic acid, 3- (4- hydroxy benzoyls) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, 1,2- ethionic acids, 2- ethylenehydrinsulfonic acids, benzene sulfonic acid, toluenesulfonic acid, 2- naphthalene sulfonic acids, 4- methyl bicycles-[2.2.2] oct-2-ene -1- carboxylic acids, glucoheptonic acid, 4,4' methylene bis-(3- hydroxyls -2- Alkene -1- carboxylic acids), 3- phenylpropionic acids, trimethylace tonitric, butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxyl naphthalene first Acid, salicylic acid, stearic acid, glutinous health acid, butyric acid, phenylacetic acid, benzenebutanoic acid, valproic acid etc.；(2) it is acid present in parent compound Proton is by metal ion such as alkali metal ion (for example, lithium, sodium, potassium), alkaline-earth metal ions (for example, magnesium or calcium) or aluminium ion The salt formed during replacement.In some cases, compound as described herein can with such as, but not limited to monoethanolamine, diethanol amine, Triethanolamine, tromethamine, N-METHYL-ALPHA-L-GLUCOSAMINE, dicyclohexyl amine, the organic base coordination of trihydroxymethylaminomethane.In other situations Under, compound as described herein can be with the amino acid forming salt such as such as, but not limited to arginine, lysine.For with including acidity The acceptable inorganic base of the compound forming salt of proton includes but is not limited to aluminium hydroxide, calcium hydroxide, potassium hydroxide, carbonic acid Sodium, sodium hydroxide etc..
It should be understood that referring to including its solvent addition form or crystal form to pharmaceutically acceptable salt, particularly molten Agent compound or polymorph.Solvate contains stoichiometry or non-stoichiometric solvent, and can be with can pharmaceutically connect Formed during the solvent received such as water, ethanol crystallization.Hydrate is formed when solvent is water, or is formed when solvent is alcohol Alcohol adduct.The solvate of compound described herein easily can be prepared or formed during process as described herein.In addition, this The compound that text is provided can exist with nonsolvated forms or solvation form.Typically for provided herein is compound and For the purpose of method, solvation form is considered to be what is be equal with nonsolvated forms.
In some embodiments, compound as described herein, as formula (I), (II), (IIa), (IIaa), (IIb), (IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、 (IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、 (IIIff), (IV), (V) or (VI) compound take various forms, and include but is not limited to, amorphous form, grinding form and receive Rice grain form.In addition, compound as described herein includes crystal form, also referred to as polymorph.Polymorph includes chemical combination The different crystal stacked arrangement of the identical element composition of thing.Polymorph often have different X-ray diffractograms, fusing point, density, Hardness, crystal shape, optical property, stability and solubility.Recrystallization solvent, crystalline rate and storage temperature etc. are a variety of Factor can cause single crystal form to account for leading.
Pharmaceutically acceptable salt, the screening of polymorph and/or solvate and sign can be using including but not limited to Heat analysis, X-ray diffraction, spectroscopic methodology, the multiple technologies of Gas Phase Adsorption and microscopy are realized.Heat analysis method is directed to heat chemistry Degraded or thermal physical process, including but not limited to polymorphic transformation, and such method be used for analysis polymorphic forms it Between relation, determine weight loss, glass transition temperature found, or for excipient Study on Compatibility.Such method bag Include but be not limited to differential scanning calorimetry (DSC), modulate differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA) and thermogravimetric With infrared analysis (TG/IR).Method of X-ray diffraction includes but is not limited to monocrystalline and powder diffractometer and synchrotron source.Institute Multiple spectrum technology includes but is not limited to Raman, FTIR, UV-VIS and NMR (liquid and solid-state).A variety of microscope skills Art includes but is not limited to polarized light microscope, the SEM (SEM) with energy dispersion X-ray analysis (EDX), tool There are EDX environmental scanning electron microscope (in gas atmosphere or water vapour atmosphere), IR microscopies and Raman microscopy.
Throughout the specification, its group and substituent may be selected to provide part and the compound of stabilization.
The use of blocking group (PG)
In reaction described here, when expecting reactive functional groups in final product, it may be necessary to protection reaction Property functional group, for example, hydroxyl, amino, imino group, sulfenyl or carboxylic group, to avoid it from unnecessarily participating in reaction.It will protect Shield group is used to block some or all of reactivity part, and prevents these groups from participating in chemical reaction until reactive base Group removes.Preferably, every kind of blocking group can be removed by different means.Cracked under entirely different reaction condition Blocking group meets the requirement of differentiation removal.
Blocking group can be removed by acid, alkali, reducing condition (such as, hydrogenolysis) and/or oxidizing condition.Such as triphen The groups such as methyl, dimethoxytrityl, acetal and t-butyldimethylsilyl are that acid is unstable, and be can be used for In the case where there is the amino group protected with Cbz groups (can be removed by hydrogenolysis) and Fmoc groups (being alkali labile) Protect carboxyl and hydroxyl reactive part.Blocked existing with acid-unstable group such as t-butylcarbamate, or with it is sour with In the case of the amine for the carbaminate end-blocking that alkali is all stablized but hydrolyzable is removed, can with such as, but not limited to methyl, ethyl and The unstable group of the alkali such as acetyl group is partially end-blocked by carboxylic acid and hydroxyl reactive.
The blocking group such as benzyl group that also can use hydrolyzable to remove is partially end-blocked by carboxylic acid and hydroxyl reactive, while with The unstable group of alkali such as Fmoc is possible to block with sour hydrogen-bonded amine groups.Carboxylic acid reaction part can be by such as herein The simple ester compounds illustrated are converted and protected, and this includes converting to Arrcostab, or can use the protection of oxidable removal Group such as 2,4- dimethoxy-benzyls are blocked, while the unstable silylamido formic acid esters of available fluoride will be deposited jointly Amino group end-blocking.
Allyl capped group is useful in the case where there is acid protecting group and alkali blocking group, because the former is It is stable and can then pass through metal or the removal of π acid catalysts.For example, in acid unstable t-butylcarbamate or alkali In the case of unstable ammonium acetate blocking group, Pd can be used0The reaction of catalysis deprotects the carboxylic acid of allyl capped.Protection Another form of group is the resin that compound or intermediate can be mutually attached therewith.As long as the residue attaches to the resin, then The functional group blocks and can not reacted.Once from resin release, the functional group can be used to reaction.
Typical end-blocking/blocking group may be selected from：
Other blocking groups, and Greene and Wuts are described in detail in available for the technology for creating and removing blocking group, Protective Groups in Organic Synthesis, the third edition, John Wiley＆Sons, New York, NY, 1999 and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994 described in, the two because Such disclosure and be incorporated by reference into this.
Disease, illness or situation
It is on the other hand the method for the pain for treating subject, it includes applying therapeutically effective amount to the subject Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、 (IIIdd), the compound of (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its is pharmaceutically acceptable Salt, pharmaceutically acceptable solvate or hydrate.It is in some embodiments the method for the pain for treating subject, It include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、 (IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、(IV)、(V) Or the compound of (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the pain Pain is relevant with postoperative pain.It is in some embodiments the method for the pain for treating subject, it is included to described tested Person apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、 (IIIcc), the compound of (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) Or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the pain and chronic Post operation Pain is relevant.It is in some embodiments the method for the pain for treating subject, it, which includes applying to the subject, treats The formula (I) of effective dose, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、 (IIId), the compound of (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmacy Upper acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the pain is relevant with neuropathic pain.One In a little embodiments for treatment subject pain method, it include to the subject using therapeutically effective amount formula (I), (II)、(IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, medicine Acceptable solvate or hydrate on, wherein the pain is relevant with postherpetic neuralgia.In some embodiments For the method for the pain for treating subject, it include to the subject using the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、 (III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、 (IIIee), the compound of (IIIf), (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, can pharmaceutically connect The solvate or hydrate received, wherein the pain is relevant with diabetic neuropathy.It is to control in some embodiments The method for treating the pain of subject, it include to the subject using the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、 (III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、 (IIIee), the compound of (IIIf), (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, can pharmaceutically connect The solvate or hydrate received, wherein the pain is relevant with HIV related neuropathies.It is in some embodiments treatment The method of the pain of subject, it include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、 (IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、 (IIIf), the compound of (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvent Compound or hydrate, wherein the pain is relevant with complex region pain syndrome.In some embodiments for treatment by The method of the pain of examination person, it include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、 (IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、 (IIIf), the compound of (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvent Compound or hydrate, wherein the pain is relevant with cancer.It is in some embodiments the method for the pain for treating subject, It include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、 (IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、(IV)、(V) Or the compound of (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the pain Pain is relevant with cancer chemotherapy.It is in some embodiments the method for the pain for treating subject, it is included to the subject Using the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、 (IIIcc), the compound of (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) Or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the pain has with neurotrosis Close.It is in some embodiments the method for the pain for treating subject, it includes applying therapeutically effective amount to the subject Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、 (IIId), the compound of (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmacy Upper acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the pain is relevant with Vulvodynia.In some realities Apply in scheme for treatment subject pain method, it include to the subject using therapeutically effective amount formula (I), (II)、(IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, medicine Acceptable solvate or hydrate on, wherein the pain is relevant with wound.In some embodiments for treatment by The method of the pain of examination person, it include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、 (IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、 (IIIf), the compound of (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvent Compound or hydrate, wherein the pain is relevant with operation.It is in some embodiments the method for the pain for treating subject, It include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、 (IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、(IV)、(V) Or the compound of (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the pain Pain is relevant with chronic musculoskeletal pain.It is in some embodiments the method for the pain for treating subject, it is included to institute State subject using the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、 (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) Compound, or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the pain and lower back Pain is relevant.It is in some embodiments the method for the pain for treating subject, it, which includes applying to the subject, treats The formula (I) of effective dose, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、 (IIId), the compound of (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmacy Upper acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the pain is closed with osteoarthritis or rheumatoid Section is scorching relevant.It is in some embodiments the method for the pain for treating subject, it, which includes applying to the subject, treats The formula (I) of effective dose, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、 (IIId), the compound of (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmacy Upper acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the pain is relevant with osteoarthritic joint inflammation. It is in some embodiments the method for the pain for treating subject, it includes applying the formula of therapeutically effective amount to the subject (I)、(II)、(IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、 (IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、 (IIIdd), the compound of (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its is pharmaceutically acceptable Salt, pharmaceutically acceptable solvate or hydrate, wherein the pain is relevant with rheumatoid arthritis.
It is in some embodiments psoriasis, pruritus, disease of itching, cancer, hypertrophy of the prostate, the wrinkle for the treatment of subject Line, nasosinusitis, rhinitis, the method for alopecia or hirsutism, it include to the subject apply therapeutically effective amount formula (I), (II)、(IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, medicine Acceptable solvate or hydrate on.It is in some embodiments the method for the psoriasis for treating subject, it is wrapped Include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、 (IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、(IV)、(V) Or the compound of (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate.In some implementations In scheme for treatment subject pruritus method, it include to the subject using therapeutically effective amount formula (I), (II)、(IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, medicine Acceptable solvate or hydrate on.It is in some embodiments the method for the disease of itching for treating subject, it includes To the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、 (IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、(IV)、(V) Or the compound of (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate.In some implementations In scheme for treatment subject cancer method, it include to the subject using the formula (I) of therapeutically effective amount, (II), (IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, medicine Acceptable solvate or hydrate on.It is in some embodiments the method for the hypertrophy of the prostate for treating subject, It include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、 (IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、(IV)、(V) Or the compound of (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate.In some implementations In scheme for treatment subject nasosinusitis method, it include to the subject using therapeutically effective amount formula (I), (II)、(IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, medicine Acceptable solvate or hydrate on.It is in some embodiments the method for the rhinitis for treating subject, it includes To the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、 (IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、(IV)、(V) Or the compound of (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate.In some implementations In scheme for treatment subject alopecia method, it include to the subject using the formula (I) of therapeutically effective amount, (II), (IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, medicine Acceptable solvate or hydrate on.It is in some embodiments the method for the hirsutism for treating subject, it is wrapped Include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、 (IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、(IV)、(V) Or the compound of (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate.
It is in some embodiments the method for the pain for treating subject, it includes using treatment having to the subject The formula (I) of effect amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、 (IIId), the compound of (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmacy Upper acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein the compound local application.In some implementations In scheme for treatment subject pain method, it include to the subject using the formula (I) of therapeutically effective amount, (II), (IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, medicine Acceptable solvate or hydrate on, wherein the compound dermal administration.In some embodiments for treatment by The method of the pain of examination person, it include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、 (IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、 (IIIf), the compound of (IIIff), (IV), (V) or (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvent Compound or hydrate, wherein the compound applied dermally.It is in some embodiments the method for the pain for treating subject, It include to the subject apply the formula (I) of therapeutically effective amount, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、 (IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、(IV)、(V) Or the compound of (VI), or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, wherein describedization Compound systemic administration.
Some terms
Unless otherwise defined, otherwise all technologies used herein and scientific terminology all have and master claimed The identical meanings being generally understood that belonging to topic.In the case where this paper terms have multiple definition, those in this section are defined.This Text quote all patents, patent application, publication and disclosed nucleotides and amino acid sequence (for example, GenBank or other Obtainable sequence in database) it is incorporated by reference into this.When quoting URL or other such identifiers or address, It should be understood that such identifier may change, and the specifying information on internet may be to die in the instant, but by searching for because of spy Net can find equal information.The availability of this information and open propagation are demonstrated to its reference.
It should be understood that foregoing general description and it is described in detail below be only it is exemplary and explanatory, be not intended to limit and want Seek any theme of protection.In this application, unless otherwise stated, the use of odd number includes plural number.It must be noted that unless Context is otherwise expressly specified, otherwise as used in specification and appended, singulative " one ", " one kind " Include a plurality of indicants with "the".In this application, unless otherwise stated, the use of "or" represents "and/or".This Outside, term " comprising " and other forms, such as " including (include) ", " include (includes) " and " contain (included) use " is not restricted.
Division header used herein is only used for organizational goal, is not necessarily to be construed as the theme described by limitation.
The definition of standard chemistry terms can be found in bibliography, be included but is not limited to, Carey and Sundberg " Advanced Organic Chemistry the 4th edition " A volumes (2000) and B volumes (2001), Plenum Press, New York. Unless otherwise indicated, conventional method includes mass spectrography, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA technology and medicine It is of science.
Unless there is provided being specifically defined, otherwise with reference to analytical chemistry as described herein, synthetic organic chemistry, medicine and medicine The nomenclature and its laboratory procedure and technology that chemistry is used all are art-recognized.Standard technique can be used for chemical synthesis, Chemical analysis, medicine preparation, preparation and delivering and treatment patient.Standard technique can be used for recombinant DNA, oligonucleotide synthesis and Tissue cultures and conversion (for example, electroporation, fat transfection).For example, the reagent of manufacturer's specification can be used in reaction and purification technique Box is carried out, or is carried out in the way of such as this area is generally realized, or is carried out as described herein.Aforementioned techniques and program generally may be used With conventional method, as quote and discuss in this manual it is various and enter referring more particularly to described in document OK.
It should be appreciated that method described herein and composition be not limited to ad hoc approach as described herein, scheme, cell line, Construct and reagent, therefore these can change.It should also be understood that terms used herein is only used for describing particular Purpose, is not intended to limit method described herein, compound, the scope of composition.
As used herein, C1-CxIncluding C1-C2、C1-C3...C1-Cx。C1-CxRefer to that the carbon for constituting its signified part is former The number of son (not including optional substituent).
" alkyl " group refers to aliphatic hydrocarbon group, and the sp3 hydridization carbon of wherein alkyl residue is attached to molecule by singly-bound Remainder.The alkyl group may include or do not include unsaturated unit.The moieties can be " saturated alkyl " group, this meaning Taste it without any unsaturated unit (that is, carbon-to-carbon double bond or carbon-to-carbon triple bond).The alkyl group can also be " unsaturated alkane Base " part, it means that it contains at least one unsaturated unit.Moieties, either saturation or unsaturated can be with It is side chain, straight chain or ring-type.
" alkyl " group can have 1 to 6 carbon atom, and (when it occurs herein, number range such as " 1 to 6 " refers to For each integer in given range；For example, " 1 to 6 carbon atom " represents that alkyl group can be by 1 carbon atom, 2 carbon originals Son, 3 carbon atoms etc. constitutes and including 6 carbon atoms until 6 carbon atoms, although this definition also contemplated not specified numerical value The appearance of the term " alkyl " of scope).The alkyl group of compound described herein can be designated as " C1-C6Alkyl " is similar Title.Only as example, " C1-C6Alkyl " represents there is one to six carbon atom in alkyl chain, i.e. alkyl chain is selected from methyl, second Base, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, n-pentyl, isopentyl, neopentyl, hexyl, propylene- 3- bases (pi-allyl), Cvclopropvlmethvl, cyclobutylmethyl, cyclopentyl-methyl, cyclohexyl methyl.Alkyl group can be substitution or It is unsubstituted.According to structure, alkyl group can be unit price or divalent group (that is, alkylidene group).
" alkoxy " refers to "-O- alkyl ", and group, wherein alkyl are as defined herein.
Term " alkenyl " refers to such alkyl group type, and the first two atom formation of the wherein alkyl group is not belonging to The double bond of aromatic group.That is, alkenyl group is from atom-C (R)=CR2Start, wherein R refers to the remainder of alkenyl group, its Can be identical or different.The non-limiting examples of alkenyl group include-CH=CH2、-C(CH3)=CH2,-CH= CHCH3,-CH=C (CH3)2With-C (CH3)=CHCH3.Alkenyl part can be side chain, straight chain or ring-type (in such case Under, it is also referred to as " cycloalkenyl group " group).Alkenyl group can have 2 to 6 carbon.Alkenyl group can be substitution or unsubstituted 's.According to structure, alkenyl group can be unit price or divalent group (that is, alkenylene group).
Term " alkynyl " refers to the first two atom three keys of formation of such alkyl group type, the wherein alkyl group. That is, alkynyl group is since atom-C ≡ C-R, and wherein R refers to the remainder of alkynyl group.The non-limiting reality of alkynyl group Example includes-C ≡ CH ,-C ≡ CCH3、–C≡CCH2CH3With-C ≡ CCH2CH2CH3." R " of alkynyl moiety can be partly side chain, Straight chain or ring-type.Alkynyl group can have 2 to 6 carbon.Alkynyl group can be substituted or unsubstituted.According to structure, alkynes Base group can be unit price or divalent group (that is, alkynylene group).
" amino " refers to-NH2Group.
Term " alkylamine " or " alkyl amino " refer to-N (alkyl)xHyGroup, wherein alkyl as defined herein, and x X=1, y=1 and x=2, y=0 are selected from y.As x=2, the nitrogen that alkyl group is attached together with them may be optionally formed Ring-type system." dialkyl amido " refers to-N (alkyl)2Group, wherein alkyl are as defined herein.
Term " aromatics " refers to the planar rings with the delocalizedπelectron system comprising 4n+2 pi-electrons, and wherein n is integer.Virtue Race's ring can be formed by five, six, seven, eight, nine or more than nine atoms.Aromatic compounds is optionally substituted.Term " aromatics " Simultaneously including aromatic yl group (for example, phenyl, naphthyl) and heteroaryl groups (for example, pyridine radicals, quinolyl).
As used herein, term " aryl " refers to such aromatic ring, wherein each atom for forming ring is that carbon is former Son.Aromatic ring can be formed by five, six, seven, eight, nine or more than nine carbon atoms.Aromatic yl group can be optionally substituted.Aromatic yl group Example include but is not limited to phenyl and naphthyl.According to structure, aromatic yl group can be unit price or divalent group (that is, arlydene Group).
As used herein, term " acyl group " refers to the group containing carbonyl moiety, and wherein the group is former via carbonyl carbon Sub-key is closed.Carbonylic carbon atom also with another carbon atom bonding, the carbon atom can be alkyl, aryl, aralkyl, cycloalkyl, miscellaneous A part for cycloalkyl, heteroaryl groups etc..
" carboxyl " refers to-CO2H.In some embodiments, carboxy moiety can be replaced by " carboxylic acid bioisostere " In generation, it is somebody's turn to do the functional group that " carboxylic acid bioisostere " refers to show the physically and/or chemically property similar with carboxylic moiety Or part.Carboxylic acid bioisostere has the biological property similar with hydroxy-acid group.Compound with carboxylic moiety Carboxylic moiety can be exchanged with carboxylic acid bioisostere, and with the compound phase containing carboxylic acid than similar physics And/or biological property.For example, in one embodiment, carboxylic acid bioisostere will be ionized under physiology pH to The degree roughly the same with hydroxy-acid group.The example of the bioisostere of carboxylic acid includes but is not limited to Deng.
Term " cycloalkyl " refers to monocyclic or polycyclic nonaromatic, wherein forming each atom (that is, skeleton original of ring Son) it is carbon atom.Cycloalkyl can be that saturation or part are undersaturated.Cycloalkyl can be with aromatic ring fusion (in such case Under, cycloalkyl is bonded by non-aromatic ring carbon atom).Group of naphthene base includes the group with 3 to 10 annular atoms.Cycloalkyl The illustrative example of group includes but is not limited to following part：, Deng.
Term " heteroaryl " or alternatively " heteroaromatic base " refer to include one or more miscellaneous originals of ring selected from nitrogen, oxygen and sulphur The aryl of son." heteroaromatic base " or " heteroaryl " containing N partly refers to the virtue that wherein at least one ring skeleton atom is nitrogen-atoms Race's group.Polyheteroaromatic group can be fusion or non-condensed.The illustrative example of heteroaryl groups includes following part：
Deng.
" Heterocyclylalkyl " group or " heterolipid ring " group refer to that wherein at least one backbone ring atoms are selected from nitrogen, oxygen and sulphur Heteroatomic group of naphthene base.The group can be with aryl or heteroaryl-condensed.The also referred to as Heterocyclylalkyl of non-aromatic heterocyclic The illustrative example of group includes：
Deng.Term heterolipid ring also includes the hydrocarbon of all loop types, includes but is not limited to single Sugar, disaccharides and oligosaccharide.Unless otherwise indicated, Heterocyclylalkyl has 2 to 10 carbon in ring.Heterocycle alkane is referred to it should be understood that working as During carbon number in base, the carbon number in the Heterocyclylalkyl is different from constituting Heterocyclylalkyl (that is, the skeleton of heterocycloalkyl ring Atom) total atom number (including hetero atom).
Term " halo " or alternatively " halogen " represent fluorine, chlorine, bromine and iodine.
Term " haloalkyl " or " halogenated alkoxy " refer to the alkyl group or alcoxyl replaced by one or more halogens Base group.Halogen may be identical or possible different.The non-limiting examples of haloalkyl include-CH2Cl、-CF3、-CHF2、- CH2CF3、-CF2CF3、-CF(CH3)2, etc..The non-limiting examples of halogenated alkoxy include-OCH2Cl、-OCF3、-OCHF2、- OCH2CF3、-OCF2CF3、-OCF(CH3)2, etc..
Term " fluoroalkyl " and " Fluoroalkyloxy " include the alkyl and alkoxy replaced by one or more fluorine atoms respectively Group.The non-limiting examples of fluoroalkyl include-CF3、-CHF2、-CH2F、-CH2CF3、-CF2CF3、-CF2CF2CF3、-CF (CH3)3, etc..The non-limiting examples of Fluoroalkyloxy group include-OCF3、-OCHF2、-OCH2F、-OCH2CF3、-OCF2CF3、- OCF2CF2CF3、-OCF(CH3)2, etc..
Term " miscellaneous alkyl " refers to such alkyl group, and wherein one or more skeletal chain atoms are selected from addition to carbon Atom, for example, oxygen, nitrogen, sulphur, phosphorus, silicon or combinations thereof.Hetero atom can be located at any interior location of miscellaneous alkyl group. Example includes, but not limited to-CH2-O-CH3、-CH2-CH2-O-CH3、-CH2-NH-CH3、-CH2-CH2-NH-CH3、-CH2-N (CH3)-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2-S(O)-CH3、- CH2-CH2-S(O)2-CH3、-CH2-NH-OCH3、–CH2-O-Si(CH3)3、-CH2- CH=N-OCH3With-CH=CH-N (CH3)- CH3.In addition, most two hetero atoms can be continuous, such as only as example ,-CH2-NH-OCH3With-CH2-O-Si(CH3)3。 In addition to number of heteroatoms, " miscellaneous alkyl " can have 1 to 6 carbon atom.
Term " key " or " singly-bound " refer to when the atom connected by key is considered as a part for larger minor structure, two Chemical bond between individual atom or two parts.
Term " part " refers to specific fragment or the functional group of molecule.Chemical part is considered as often in embedded molecule or attached In the chemical entities of the molecule.
As used herein, oneself occur and refer to be selected from alkyl, alkyl halide without the substituent " R " that numeral is represented Base, miscellaneous alkyl, alkenyl, cycloalkyl, aryl, the substituent of heteroaryl (being bonded by ring carbon) and Heterocyclylalkyl.
Term " optionally substituted " or " substituted " refer to that referenced group can be taken by one or more other groups Generation, one or more other groups individually and separately selected from alkyl, cycloalkyl, aryl, heteroaryl, Heterocyclylalkyl ,- OH, alkoxy, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone, aryl sulfone ,-CN, alkynes, C1- C6Alkyl alkynes, halo, acyl group, acyloxy ,-CO2H、-CO2- alkyl, nitro, haloalkyl, fluoroalkyl, Fluoroalkyloxy, and ammonia Base, including monosubstituted and disubstituted amino group (such as-NH2、-NHR、-N(R)2) and its protected derivative.At some In embodiment, optional substituent is independently selected from halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2 Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, Aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.In some embodiments, appoint The substituent of choosing is independently selected from halogen ,-CN ,-NH2、-OH、-NH(CH3)、-N(CH3)2、-CH3、-CH2CH3、-CF3、-OCH3 With-OCF3.In some embodiments, substituted group is by one or more foregoing substituent groups.In some embodiments, It is optional on aliphatic carbon atom (non-annularity or ring-type, saturation or undersaturated carbon atom, in addition to aromatic carbon atoms) Substituent includes oxo (=O).
Method described herein and preparation including the use of with formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、 (IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、 (IV), the crystal form (also referred to as polymorph) or pharmaceutically acceptable salt of the compound of (V) or (VI) structure, and tool There is the active metabolite of these compounds of same type activity.In some cases, compound can be deposited with dynamic isomer .All dynamic isomers are all included in the range of compound illustrated herein.In addition, compound as described herein can be with Nonsolvated forms and solvation form exist together with pharmaceutically acceptable solvent such as water, ethanol.It is additionally considered that herein The solvation form of the compound shown is disclosed herein.
Term " medicine box " and " product " are synonymously used.
Term " subject " or " patient " include mammal and nonmammalian.The example of mammal includes but not limited In any member of mammal：People, non-human primate such as chimpanzee and other apes and monkey class；Farm-animals are such as Ox, horse, sheep, goat, pig；Domestic animal such as rabbit, dog and cat；Experimental animal, including rodent such as rat, mouse and cavy Deng.The example of nonmammalian includes but is not limited to bird, fish etc..Provided herein is method and composition an embodiment In, mammal is behaved.
As used herein, term " treatment (treat) ", " treatment (treating) " or " treatment (treatment) " bag Include alleviation, mitigation or improve disease or condition symptoms, prevention other symptoms, the potential cause for improving or preventing symptom, suppression disease Disease or situation, for example, preventing the development of disease or situation, mitigating disease or situation, cause disease or situation to disappear, mitigate by disease Situation caused by disease or situation, or preventative and/or therapeutic the symptom for stopping disease or situation.
As used herein, specified disease, illness or situation are improved by applying specific compound or pharmaceutical composition Symptom refer to be attributable to the administration of the compound or composition or any mitigation of associated seriousness, breaking-out and prolong Late, progress slows down, or the duration shortening, it is either permanent or temporary transient, continue or of short duration.
As used herein, term " regulation " refers to the work for directly or indirectly interacting to change target protein with target protein Property, only as example, include the activity of the activity of suppression target or limitation or reduction target.
As used herein, term " conditioning agent " refers to the compound for changing target activity.For example,
Compared with active value in the presence of not conditioning agent, conditioning agent can cause certain active value of target Increase reduces.In certain embodiments, conditioning agent is the inhibitor of the value for the one or more activity for reducing target. In some embodiments, inhibitor prevents the one or more activity of target completely.
As used herein, for preparation, composition or composition term " acceptable " refers to being treated The not lasting adverse effect of the general health of subject.
As used herein, " pharmaceutically acceptable " refers to the biological activity or property for not eliminating compound and relative Nontoxic material, such as carrier or diluent, i.e. the material can be applied to individual without causing undesirable biology effect or not Any component with the composition comprising the compound interacts in harmful manner.
As used herein, term " drug regimen " refers to the production produced by the mixing more than a kind of active component or combination Thing, and it includes the fixed Combination and non-fixed combinations of active component.Term " fixed Combination " refers to a kind of active component for example Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee), (IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、 (IIIdd), both the compound and assistant agent of (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) are with single The form of entity or dosage is administered simultaneously to patient.Term " non-fixed combinations " refer to a kind of active component such as formula (I), (II), (IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the compound and assistant agent of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) as single entity simultaneously, Patient sequentially is applied to parallel or without specific interval time restriction, wherein such be applied in patient's body provides two kinds of changes The level of significance of compound.The latter applies also for HAART, for example, the administration of three or more active components.
Term " pharmaceutical composition " refer to formula as described herein (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、 (IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、 (IV), compound and other chemical constituents such as carrier, stabilizer, diluent, dispersant, suspending agent, the thickener of (V) or (VI) And/or the mixture of excipient.Pharmaceutical composition contributes to administration of the compound to organism.The technology of a variety of administration compounds It is present in this area, includes but is not limited to：It is intravenous apply, orally administer, aerosol administration, parenteral administration, ophthalmology are applied With, pulmonary administration and local application.
Term " Capsaicinoids or capsaicin analog " is intended to be included in the discontinuous partial zones for being responsible for triggering pain The high localized destruction of the selectivity of generation C- fibers and/or A- δ-fiber or Disability in domain, to eliminate by the position Put caused pain, at the same make C- fibers and/or A- δ-fiber activation outside pain position and/or damage it is potential it is bad after Any compound that fruit minimizes, such as (E)-capsaicine, superpower Capsaicin (resinifiatoxin), AM-404 (N- (4- hydroxyls Phenyl) -5Z, 8Z, 11Z, 14Z- eicosatetraenamides), N-Arachidonylethanolamine, Arvanil, the superpower Capsaicin of 6 '-iodine, NADA (N- arachidonic bases dopamine), OLDA (N- oleoyls dopamine), Olvanil and PPAHV (phorbol 12s-phenylacetate 13- acetic acid esters 20- homovanillic acid ester).Include, but not limited to N- for other suitable Capsaicinoids as described herein Vanillylnonanamides, N- vanillylsulfonamides, N- vanillyls urea, N- vanillyls carbamate, N- [(substituted phenyl) first Base] alkylamide, methylene substitution N- [(substituted phenyl) methyl] alkane acid amides, N- [(substituted phenyl) methyl]-cis- Single saturation acrylamide, N- [(substituted phenyl) methyl] two unsaturated amides, 3- hydroxyacetanilides, hydroxy phenyl acetamide, Pseudo- capsaicine, Dihydrocapsaicin, nordihydrocapsaicin, high capsaicine, high Dihydrocapsaicin I, N-Arachidonylethanolamine, pepper Alkali, zingiberone, happy wooden aldehyde (warburganal) living, polygodial (polygodial), Aframodial (aframodial), meat Osmanthus dialdehyde (cinnamodial), cinnamosmolide, cinnamolide, cassia bark lactone, Nonivamide, N- oil bases-high-quality slender joss stick Oxamides, isovelleral, scalaradial, ancistrodial, β-acaridial, merulidial, Scutigeral and any combination of them or mixture.
As used herein, term " TRPV1 activators " refers to the acceptor of activation transient receptor potential class Vanillin 1 (TRPV1) compound or composition.TRPV1 activators include but is not limited to capsaicine, Dihydrocapsaicin, drop dihydro capsicum Plain, high Dihydrocapsaicin, high capsaicine, Dihydrocapsaicin, Nonivamide and resin gliotoxin (resiniferatoxin).
As used herein, term " effective dose " or " therapeutically effective amount " refer to the enough medicaments or chemical combination applied Thing, it treats one or more symptoms of disease or situation by mitigating to a certain extent.As a result can be disease signs, disease The reduction and/or alleviation of shape or the cause of disease, or biosystem any other it is desired change.For example, " having for therapeutical uses Effect amount " be comprising formula described herein (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、 (IIIcc), the compound of (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) Composition provides the amount needed for the clinically significant reduction of disease symptomses.Under any individual cases, suitable " effective " amount Determined using technologies such as dose escalation studies.
As used herein, term " enhancing (enhance) " or " enhancing (enhancing) " refer to desired effects effect or The increase or extension of duration.Accordingly, with respect to the effect for improving therapeutic agent, term " enhancing " referred in effect or duration Aspect increases or extended ability of the other therapeutic agents to the effect of system.As used herein, " enhancing effective dose " refers to be enough Strengthen the amount of effect of another therapeutic agent in desirable system.
As used herein, term " co-administration " etc. is intended to include selected administration of the therapeutic agent to single patient, and It is intended to include such therapeutic scheme, its Chinese medicine is applied by identical or different route of administration or when identical or different Between applied.
As used herein, term " carrier " refers to contribute to the relative nontoxic being incorporated to compound in cell or tissue Compound or medicament.
Term " diluent " refers to the chemical compound for before delivery being diluted compound of interest.Because dilute More stable environment can be provided by releasing agent, so they can be additionally used in stable compound.It is dissolved in salt (its in cushioning liquid PH controls or maintenance can be provided) it is used as the diluent of this area, including but not limited to phosphate buffered salt solution.
" metabolin " of compound disclosed herein is the derivative of the compound formed when compound is metabolized.Art Language " active metabolite " refers to the biologically active derivatives of the compound formed during compound metabolism.As used herein, art Language " metabolism " refers to the process of predetermined substance by organism transform (including but is not limited to hydrolysis and the reaction by enzymatic) Summation.Therefore, enzyme can make compound produce specific structural change.For example, a variety of oxidations of Cytochrome P450 catalysis are also Original reaction, and the glucuronic acid molecules that have activated of UDP glucuronic acid transfer enzymatic be changed into aromatic alcohol, aliphatic alcohol, Carboxylic acid, amine and free thiohydroxy group.Other can be from The Pharmacological Basis of on the information of metabolism Therapeutics, the 9th edition, McGraw-Hill (1996) is obtained.The metabolin of compound disclosed herein can be by place Main administration compound and analyzing differentiates from the tissue sample of host, or by the way that compound is incubated in vitro together with liver cell And analyze gained compound and differentiate.
" bioavilability " refer to compound disclosed herein (for example, formula (I), (II), (IIa), (IIaa), (IIb), (IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、 (IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、 (IIIff), (IV), (V) or (VI) compound) it is delivered to the weight percent in the overall circulation of studied animal or people Than.Total exposure (AUC (0- ∞)) of medicine during intravenous administration is often defined as 100% bioavilability (F%).It is " oral raw Thing availability " refers to that compared with intravenous injection compound disclosed herein is absorbed into overall follow during drug composition oral Degree in ring.
" plasma concentration " refer to formula (I) disclosed herein in the plasma component of subject's blood, (II), (IIa), (IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、 (III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、 (IIIee), the concentration of (IIIf), (IIIff), (IV), (V) or (VI) compound.It should be understood that due to metabolism changeability and/ Or the possible interaction with other therapeutic agents, the plasma concentration of compound described herein can significantly become between subjects Change.According to an embodiment disclosed herein, the plasma concentration of compound disclosed herein can change with subject.It is similar Ground, such as maximal plasma concentration (Cmax) are reached under time (Tmax) or the plasma concentration time curve of maximal plasma concentration The gross area (AUC (0- ∞)) equivalence can change with subject.Due to this changeability, " therapeutically effective amount " of compound is constituted Required amount can change with subject.
As used herein, " improvement " refers to disease or the improvement of situation or the symptom related to disease or situation at least Alleviate part.
Pharmaceutical composition and application process
Can use helps physiologically may be used the one or more that reactive compound is processed into pharmaceutically usable preparation The carrier (including excipient and auxiliary agent) of receiving, in a usual manner compounding pharmaceutical composition.Appropriate preparation depends on selected Route of administration.For example, the other details on the appropriate excipients for pharmaceutical composition described herein can be Remington:The Science and Practice of Pharmacy, the 19th edition (Easton, Pa.:Mack Publishing Company,1995)；Hoover,John E.,Remington’s Pharmaceutical Sciences, Mack Publishing Co.,Easton,Pennsylvania 1975；Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker,New York,N.Y.,1980；And Pharmaceutical Dosage Forms and Drug Delivery Systems, the 7th edition (Lippincott Williams＆Wilkins, 1999) in find, it is incorporated by reference into this because of these disclosures.
As used herein, pharmaceutical composition refer to formula as described herein (I), (II), (IIa), (IIaa), (IIb), (IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、 (IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、 (IIIff), (IV), (V) or (VI) compound and other chemical constituents for example carrier, stabilizer, diluent, dispersant, suspending agent, The mixture of thickener and/or excipient.Pharmaceutical composition contributes to administration of the compound to organism.Implement provided herein is Treatment or during application method, the compound described herein of therapeutically effective amount is applied to be treated with pharmaceutical composition The subject of disease, illness or situation.In some embodiments, subject behaves.Therapeutically effective amount can be according to the tight of disease Principal characteristic, the age of subject and relative healths, the effect of compound used therefor and other factors and it is widely varied.Formula (I), (II), (IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) can be used alone, or as mixture into Divide with one or more therapeutic agents to be applied in combination (such as in conjoint therapy).
Pharmaceutical preparation as described herein can be applied to subject by a variety of route of administration, include but is not limited to, orally apply Applied with approach, parenteral (for example, intravenous, subcutaneous, intramuscular) route of administration, intranasal administration approach, buccal route of administration, part With approach, rectal administration approach or applied dermally approach.In addition, comprising formula (I), (II), (IIa), (IIaa), (IIb), (IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、 (IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、 (IIIff), the pharmaceutical composition described herein of (IV), (V) or (VI) compound can be formulated into any suitable formulation, including But be not limited to, aqueous oral dispersion, liquid, gel, syrup, elixir, slurries, suspension, aerosol, control release preparation, Fast melt formulations, effervescent formulation, lyophilized formulations, tablet, pulvis, pill, dragee, capsule, delay delivery formulations, extension release Put preparation, pulsation-releasing preparation, many granular preparations, and the immediate release formulation and control release preparation mixed.
The compound and/or composition can be applied by part in the way of non-systemic, for example, via compound is straight Connect and be injected in organ or tissue, generally in the form of depot formulation.Such preparation can be by implantation (for example, subcutaneous or flesh Meat is implanted into) or applied by intramuscular injection.In addition, medicine can be made in the form of quick-release formulation, to extend release The form of agent is provided in the form of immediate release formulation.
Pharmaceutical composition including compound described herein can be manufactured in a usual manner, such as only as example, be passed through Conventional mixing, dissolving, granulation, dragee manufacture, water mill, emulsification, encapsulation, embedding or compression process manufacture.
Pharmaceutical composition will comprising at least one formula (I) described herein, (II), (IIa), (IIaa), (IIb), (IIbb), (IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、 (IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、 (IV), (V) or (VI) compound, is used as the activity in free acid or the form of free alkali form or pharmaceutically acceptable salt Composition.In addition, method described herein and pharmaceutical composition are including the use of crystal form (also referred to as polymorph) and have The active metabolite of these compounds of same type activity.In some cases, compound can exist with dynamic isomer. All dynamic isomers are all included in the range of compound illustrated herein.In addition, compound as described herein can be with non- Solvation form and solvation form exist together with pharmaceutically acceptable solvent such as water, ethanol.It is additionally considered that and shows herein The solvation form of the compound gone out is disclosed herein.
In certain embodiments, provided herein is composition can also suppress microorganism comprising one or more preservatives Activity.Suitable preservative includes quaternary ammonium compound, such as benzalkonium chloride, cetab and hexadecyl pyrrole Pyridine.
Can by by one or more solid excipients and one or more compounds described herein (for example, formula (I), (II)、(IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI)) mixing, it is mixed optionally obtained by grinding Compound, and if desired, then addition suitable auxiliary agents post-processing granulated mixtures to obtain tablet, pill or capsule, from And obtain pharmaceutical preparations for oral use.Suitable excipient includes, for example, filler such as sugar, including lactose, sucrose, Mannitol or D-sorbite；Cellulose preparation such as cornstarch, wheaten starch, rice starch, farina, bright Glue, bassora gum, methylcellulose, microcrystalline cellulose, hydroxypropyl methyl cellulose, sodium carboxymethylcellulose；Or other fillers Such as：Polyvinylpyrrolidone (PVP or PVP) or calcium phosphate.If desired, disintegrant can be added, such as crosslinking carboxylic first of crosslinking Base sodium cellulosate, polyvinylpyrrolidone, agar, or alginic acid or its salt such as sodium alginate.
Suitable coating is provided for sugar-coat capsule core.Therefore, the sugar juice of concentration can be used, the concentrated sugar solution is optionally Containing Arabic gum, talcum, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and/or titanium dioxide, paint solution and Suitable organic solvent or solvent mixture.Dyestuff or pigment can be added to for identification in tablet or dragee coatings, Or for characterizing the various combination of active compound doses.
The orally available pharmaceutical preparation used includes the sucking fit capsule that is made up of gelatin, and by gelatin and plasticiser such as The soft seal capsule that glycerine or D-sorbite are made.Sucking fit capsule can contain with filler such as lactose, adhesive such as starch, And/or lubricant such as talcum or magnesium stearate, and the active component that optional stabilizer is mixed.In soft capsule, activation Compound can dissolve or be suspended in suitable liquid such as fat oil, atoleine or liquid macrogol.In addition, stabilization can be added Agent.
In some embodiments, solid dosage forms disclosed herein can for tablet form (including suspension tablet, fast fast thawing Change tablet, occlusion disintegrating tablet, rapid disintegration tablet, effervescent tablet or caplet agent), pill, pulvis (include the powder of aseptic packaging Agent, assignable pulvis or effervesce pulvis), capsule (including soft capsule or hard shell capsules, for example, gelatin or plant by animal origin The capsules that are made of HPMC in thing source, or " spreading capsule "), solid dispersions, solid solution, bioerodible formulation, control Delivery formulations, pulsed release dosage form, many bead dosage forms, micropill, granule or aerosol.In other embodiments, the medicine Preparation is powder form.In other another embodiments, pharmaceutical preparation is tablet form, including but not limited to rapid melting piece Agent.In addition, the pharmaceutical preparation of compound described herein can be applied in the form of single capsule or multiple capsule formulations.At some In embodiment, the pharmaceutical preparation is applied in the form of two or three or four capsules or tablet.
In some embodiments, by by formula described herein (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、 (IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、 (IV), the particle of (V) or (VI) compound mixes to form bulk blend composition to prepare with one or more excipient Solid dosage forms, for example, tablet, effervescent tablet and capsule.When it is homogeneous to refer to these bulk blended mixts, it is intended that herein The formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、 (IIId), the particle of (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) compound is equably Disperse in the composition so that composition can be subdivided into equivalent unit dosage forms, such as tablet, pill and capsule.Single unit Dosage can also include film coating, and the film coating is decomposed in orally ingestible or when being contacted with diluent.These preparations can pass through It is prepared by routine pharmacological technology.
Pharmaceutical solid dosage forms as described herein can comprising formula as described herein (I), (II), (IIa), (IIaa), (IIb), (IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、 (IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、 (IIIff), (IV), (V) or (VI) compound, and one or more pharmaceutically acceptable additives, such as, compatibility are carried Body, adhesive, filler, suspending agent, flavor enhancement, sweetener, disintegrant, dispersant, surfactant, lubricant, colouring agent, Diluent, solubilizer, wetting agent, plasticiser, stabilizer, penetration enhancer, wetting agent, antifoaming agent, antioxidant, preservative, Or their one or more combinations.Another in terms of other, using such as Remington's Pharmaceutical Sciences, the standard envelope program of those described in the 20th edition (2000), the preparation around compound described herein is provided Film coating.In one embodiment, some or all particles of compound described herein have been coated.In another embodiment In, by some or all particle microencapsulations of compound described herein.In yet another embodiment, compound described herein Particle is not microencapsulation and is uncoated.
Suitable carrier for solid dosage forms described herein include but is not limited to Arabic gum, gelatin, cataloid, Calcium glycerophosphate, calcium lactate, maltodextrin, glycerine, magnesium silicate, casein sodium, soybean lecithin, sodium chloride, tricresyl phosphate Calcium, dipotassium hydrogen phosphate, stearoyl lactate, carrageenan, monoglyceride, diglyceride, pregelatinized starch, hydroxypropyl methyl are fine Tie up element, hydroxypropyl methyl cellulose acetate stearate, sucrose, microcrystalline cellulose, lactose, mannitol etc..
Suitable fillers for solid dosage forms described herein include but is not limited to lactose, calcium carbonate, calcium phosphate, phosphoric acid hydrogen Calcium, calcium sulfate, microcrystalline cellulose, cellulose powder, dextrose, dextrates, glucan, starch, pregelatinized starch, hydroxyl Propyl methocel (HPMC), HPMCP, hydroxypropyl methyl cellulose acetate are stearic Acid esters (HPMCAS), sucrose, xylitol, lactitol, mannitol, D-sorbite, sodium chloride, polyethylene glycol etc..
In order to as efficiently as possible from solid dosage forms matrix release formula (I), (II), (IIa), (IIaa), (IIb), (IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、 (IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、 (IIIff) disintegrant often is used in, (IV), (V) or (VI) compound, preparation, especially when formulation adhesive compresses.When When moisture is absorbed into the formulation, disintegrant contributes to by being swelled or capillarity disrupting agent mold base.For herein The Suitable disintegrators of described solid dosage forms include but is not limited to native starch such as cornstarch or farina, pregelatinated and formed sediment Powder such as National 1551 orOr sodium starch glycollate is such asOrCellulose Such as woodwork, methyl avicel cellulose, for example,PH101、PH102、 PH105、P100、MingWithMethylcellulose, The sodium carboxymethylcellulose of cross-linked carboxymethyl cellulose or the cellulose of crosslinking, such as crosslinkingCrosslinking Carboxymethyl cellulose, or crosslinking cross-linked carboxymethyl cellulose, crosslinking starch such as primojel, be crosslinked polymer such as Crospovidone, the polyvinylpyrrolidone of crosslinking, the salt such as sodium alginate, clay of alginate such as alginic acid or alginic acid are such asHV (aluminium-magnesium silicate), glue such as agar, guar gum, locust bean gum, Karaya Gum, pectin or bassora gum, hydroxyl second Acid-starch sodium, bentonite, natural sponge, surfactant, resin such as cationic ion-exchange resin, citrus pulp, dodecyl sulphate Combination of sodium, lauryl sodium sulfate and starch, etc..
Adhesive is that solid oral dosage formulations assign caking property：For powder filled capsule preparation, they help to be formed The embolism into soft shell capsule or hard-shell capsule can be filled, for tablet formulation, they ensure that the tablet has been kept upon compression It is whole and help ensure that compression or filling step before blending homogeneity.It is suitable as the adhesive in solid dosage forms described herein Material include but is not limited to carboxymethyl cellulose, methylcellulose (for example,), hydroxypropyl methyl cellulose (for example, hydroxypropyl methylcellulose USP Pharmacoat-603, hydroxypropyl methyl cellulose acetate stearate (Aqoate HS-LF and HS), hydroxyethyl cellulose, hydroxypropyl cellulose (for example,), ethyl cellulose (for example, ) and microcrystalline cellulose (for example,), crystallite dextrose, amylose, aluminium-magnesium silicate, many saccharic acids, bentonite, gelatin, Polyvinylpyrrolidone//vinyl acetate copolymer, Crospovidone, PVP, starch, pregelatinized starch, bassora gum, dextrin, Sugar such as sucrose (for example,), glucose, dextrose, molasses, mannitol, D-sorbite, xylitol (for example,), lactose, natural or synthetic glue is such as Arabic gum, bassora gum, ghatti gum, isapgol husk (isapol husks) Mucus, starch, polyvinylpyrrolidone (for example,CL、CL、XL-10 WithK-12), larch arabinogalactan,Polyethylene glycol, wax, sodium alginate etc..
Generally, 20-70% binder levels are used for the gelatin capsule formulation that powder is filled.Bonding in tablet formulation Agent use level is with direct compression, wet granulation, roll-in or other excipient as itself can be as the filler of medium adhesive Using and change.In some embodiments, the binder levels that people determines preparation are prepared, but 70% is up in tablet formulation Adhesive use level is common.
Proper lubrication agent or glidant for solid dosage forms as described herein include but is not limited to stearic acid, hydroxide It is calcium, talcum, cornstarch, sodium stearyl fumarate, alkali and alkaline earth metal ions salt (such as aluminium salt, calcium salt, magnesium salts, zinc salt), hard Resin acid, odium stearate, magnesium stearate, zinc stearate, wax,It is boric acid, sodium benzoate, sodium acetate, sodium chloride, bright Propylhomoserin, polyethylene glycol or methoxy poly (ethylene glycol) such as CarbowaxTM, PEG 4000, PEG 5000, PEG 6000, propane diols, oil Sour sodium, glyceryl behenate, glyceryl palmitostearate, benzoic acid glyceride, lauryl magnesium sulfate or lauryl sulphur Sour sodium etc..
Suitable diluents for solid dosage forms as described herein include but is not limited to sugar (including lactose, sucrose and grape Sugar), polysaccharide (including dextrates and maltodextrin), polyalcohol (including mannitol, xylitol and D-sorbite), Cyclodextrin etc..
Suitable humectants for solid dosage forms as described herein include, for example, oleic acid, glycerin monostearate, dehydration Sorbitol monooleate, sorbitan monolaurate, Emulphor FM, polyoxyethylene sorbitan list Oleate, Tween 20, quaternary ammonium compound are (for example, Polyquat), enuatrol, the moon Osmanthus base sodium sulphate, magnesium stearate, docusate sodium, glyceryl triacetate, vitamin E TPGS etc..
Suitable surfactant for solid dosage forms as described herein includes, for example, NaLS, anhydrosorbitol Sorbitane monooleate, Polysorbate 80, polysorbate, poloxamer, bile salt, monostearate The copolymer of glyceride, oxirane and expoxy propane is for example(BASF) etc..
Suitable suspending agents for solid dosage forms as described herein include but is not limited to polyvinylpyrrolidone, such as poly- second Alkene pyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidone K25 or PVP K30, polyethylene glycol (such as polyethylene glycol can have about 300 to about 6000, or about 3350 to about 4000, or about 5400 to about 7000 molecular weight), Vinyl pyrrolidone/vinyl acetate copolymer (S630), sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methyl are fine Tie up element, Polyoxyethylene Sorbitan Monooleate, hydroxyethyl cellulose, sodium alginate, such as glue, bassora gum and Arabic gum, cluster bean Glue, Xanthan gum (including xanthans), sugar, such as cellulosic material, sodium carboxymethylcellulose, methylcellulose, carboxymethyl Sodium cellulosate, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, Polyoxyethylene Sorbitan Monooleate, sodium alginate, polyethoxylated dehydration D-sorbite monolaurate, polyethoxylated sorbitan monolaurate, PVP etc..
Appropriate surfaces antioxidant for solid dosage forms as described herein includes, for example, Yoshinox BHT (BHT), sodium ascorbate and tocopherol.
Exist between the additive used in solid dosage forms as described herein sizable overlapping.Therefore, it is outlined above Additive should be regarded as merely the exemplary and unrestricted solid dosage forms for being comprised in pharmaceutical composition described herein In additive type.
In other embodiments, one or more layers of pharmaceutical preparation is plasticized.Illustratively, plasticiser is often higher boiling Solid or liquid.About 0.01% to about 50% suitable plasticiser can be added based on coated composition weight (w/w).Plasticiser Including but not limited to diethyl phthalate, citrate, polyethylene glycol, glycerine, acetylated glycerides, glyceryl triacetate, poly- third Glycol, polyethylene glycol, triethyl citrate, dibutyl sebacate, stearic acid, stearyl alcohol, stearate and castor oil.
Compressed tablets is the solid dosage forms by compressing the bulk blend of above-mentioned preparation and preparing.In multiple embodiments In, being designed to will be comprising one or more flavor enhancement in orally-dissolvable compressed tablets.In other embodiments, compressed tablets The film around final compressed tablets will be included.In some embodiments, film coating can provide formula as described herein (I)、(II)、(IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、 (IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、 (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) compound are from the sustained release in preparation. In other embodiments, film coating contribute to patient's compliance (for example,It is coated or sweet tablet).IncludingFilm coating inside is usually about the 1% to about 3% of tablet weight.In other embodiments, compressed tablets Include one or more excipient.
For example, capsule can be prepared by the way that the bulk blend of the preparation of above-claimed cpd is placed in capsule.One In a little embodiments, preparation (non-aqueous suspensions and solution) is placed in Perle.In other embodiments, make Agent is placed in standard gelatin capsule or the non-gelatin capsules such as capsule comprising HPMC.In other embodiments, preparation quilt It is placed in spreading capsule, wherein can integrally swallow the capsule, or the capsule can be opened and with before the meal spilling content On food.In some embodiments, therapeutic dose is divided into multiple (for example, two, three or four) capsules.At some In embodiment, all dosage of preparation is delivered all in the form of capsule.
In various embodiments, by formula as described herein (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、 (IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、(IIIff)、 (IV), the particle of (V) or (VI) compound and one or more excipient dry blends and compress blocking such as tablet, the block it is hard Degree be enough after oral administration be less than about 30 minutes, less than about 35 minutes, less than about 40 minutes, less than about 45 minutes, be less than about 50 minutes, less than about 55 minutes or less than about 60 minutes within produce the pharmaceutical composition being substantially disintegrated so that by said preparation Release is into gastrointestinal fluid.
On the other hand, formulation can include the preparation of microencapsulation.In some embodiments,
There are one or more other compatible materials in microencapsulation material.Exemplary material includes but is not limited to pH tune Save agent, corrode accelerator, antifoaming agent, antioxidant, flavor enhancement and carrier mass such as adhesive, suspending agent, disintegrant, filling Agent, surfactant, solubilizer, stabilizer, lubricant, wetting agent and diluent.
Material for microencapsulation as described herein includes the material compatible with compound described herein, and it fully will Compound excipient incompatible with other is isolated.The material compatible with compound described herein be delay formula (I), (II), (IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), those materials of the internal release of the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI).
The Exemplary microcapsules compound matter of release for delaying the preparation comprising compound described herein includes but not limited In hydroxypropylcelluloether ether (HPC) such asOr Nisso HPC, low-substituted hydroxypropyl cellulose ether (L-HPC), hydroxypropyl Methyl cellulose ether (HPMC) (such as Seppifilm-LC,Metolose SR、 Opadry YS, PrimaFlo, Benecel MP824 and Benecel MP843), methyl cellulose polymers such asHydroxypropyl methyl cellulose acetate stearate Aqoat (HF-LS, HF-LG, HF-MS) andEthyl cellulose (EC) and its mixture (such as E461,)、 Polyvinyl alcohol (PVA) such as Opadry AMB, hydroxyethyl cellulose are such asCarboxymethyl cellulose and carboxymethyl cellulose Salt (CMC) such asPolyvinyl alcohol and ethylene glycol copolymer such as Kollicoat, monoglyceride (Myverol), triglyceride (KLX), polyethylene glycol, Modified Food Starch, acrylate copolymer and acrylate copolymer with The mixture of cellulose ether is (such asEPO、L30D-55、FS 30DL100-55、L100、S100、RD100、 E100、L12.5、S12.5、NE30D andNE 40D), adjacent benzene Dioctyl phthalate cellulose acetate, sepifilms such as HPMC and stearic mixture, cyclodextrin and these materials mixture.
In yet another embodiment, plasticiser such as polyethylene glycol is mixed in microencapsulation material, for example, PEG 300, PEG 400, PEG 600, PEG 1450, PEG 3350 and PEG 800, stearic acid, propane diols, oleic acid and glyceryl triacetate.At it In his embodiment, for delaying the microencapsulation material of release of pharmaceutical composition to come from USP or NF (NF). In other another embodiments, microencapsulation material is Klucel.In other another embodiments, microencapsulation material is first Base cellulose (methocel).
Microencapsulation compound as described herein can by including such as spray drying process, rotating disk-solvent method, hot melt, Spray cooling, fluid bed, electrostatic precipitation, centrifugation extrusion, rotatable suspension separation, at liquid-gas method or solid-air interface polymerization, Method including pressure extrusion or spraying solvent extraction bath is prepared.In addition to that, several chemical technologies, example be it is also possible to use Such as, multiple cohesion, solvent evaporation, Polymer-Polymer incompatibility, the interfacial polymerization in liquid medium, in-situ polymerization, in liquid Dry, and the desolvation in liquid medium.In addition, it is possible to use other method, such as roll-in, extrusion/round as a ball, condense or receive Rice grain is coated.
, can also be according to preparing effervesce powder in the disclosure in other another embodiments.Salia effervescentia has been used for medicine Thing is dispersed in water to orally administer.Salia effervescentia is granule or coarse powder containing the medicament in drying composite, generally It is made up of sodium acid carbonate, citric acid and/or tartaric acid.When such salt is added to the water, bronsted lowry acids and bases bronsted lowry reaction discharges dioxy Change carbon gas, so as to cause " effervesce ".The example of salia effervescentia includes such as following component：Sodium acid carbonate or sodium acid carbonate and carbonic acid The mixture of sodium, citric acid and/or tartaric acid.Any soda acid for causing carbon dioxide to discharge combination is used equally for replacing bicarbonate The combination of sodium and citric acid and tartaric acid, as long as the composition is applied to pharmaceutical applications and produces about 6.0 or higher pH.
In other embodiments, the preparation described herein comprising compound described herein is solid dispersions.Prepare The method of such solid dispersions include but is not limited to for example U.S. Patent No. 4,343,789, No. 5,340,591, No. 5,456,923, No. 5,700,485, No. 5,723,269 and U.S. Patent Publication the 2004/0013734th.Another In other embodiments, preparation described herein is solid solution.Solid solution merges material with activating agent and other excipient Together so that cause medicine to dissolve mixture heating, then by resulting composition cooling to produce solids blend, this is consolidated Body blend can further be configured to capsule or be added directly in capsule or compress piece agent.The such solid solution of production Method includes but is not limited to such as U.S. Patent No. 4,151,273, No. 5,281,420 and No. 6,083,518.
Drug oral solid dosage forms comprising the preparation described herein containing compound described herein can be prepared further, With provide formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、 (IIId), the control of the compound of (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) is released Put.Control release refers to the formulation that compound described herein is mixed within the period of extension according to required release profiles from it In release.For example, control release curve includes sustained release, extension release, pulse release and sustained release curve.With immediately Release composition is compared, control release composition allow according to predetermined curve within the period of extension by drug delivery to tested Person.Such rate of release can provide the medicament for the treatment of level of significance within the period of extension, so that the fast quick-release with routine Formulation is put compared to the longer pharmacology response time is provided, while minimizing side effect.This longer response time provides The many intrinsic benefits that can not be realized with corresponding short-acting immediate release formulation.
In some embodiments, solid dosage forms as described herein can be formulated into enteric coating sustained release oral agents Type, i.e. the mouth of the pharmaceutical composition described herein for the release for being formulated as realizing using enteric coating in the small intestine of intestines and stomach Oral dosage form.The formulation of enteric coating can be (itself to be cladding containing active component and/or other composition components or be not coated with bag Cover) granule, powder, micropill, bead or the compression of particle or molding or extrusion tablet/molding piece (cladding or do not wrap Cover).Enteric coating peroral dosage form can also be containing cladding itself or uncoated solid carrier or the micropill of composition, bead Or the capsule of granule (cladding is uncoated).
As used herein, term " quick release " or " sustained release " refer to allow release with generally predictable The delivering that given pace is completed.In some embodiments, the method for sustained release is that regulation intramolecular cyclization release is anti- Or the initiation of intramolecular cyclization release reaction should be improved via addition buffer solution.
, can also be by colouring agent, antitack agent, surfactant, antifoaming agent, lubricant (for example, Brazil in addition to plasticiser Palm wax or PEG) added in being coated to dissolve or disperse and improve to be coated performance and the product that is coated coating material.
In other embodiments, using pulsed dosage forms delivering comprising formula as described herein (I), (II), (IIa), (IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、 (III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、 (IIIee), the preparation as described herein of the compound of (IIIf), (IIIff), (IV), (V) or (VI).Pulsed dosage forms can be Predetermined point of time after the lag time of control provides at privileged site and one or more discharges pulse immediately.Pulse agent Type can be applied using a variety of pulse preparations, be included but is not limited to, U.S. Patent No. 5,011,692；No. 5,017,381； No. 5,229,135；No. 5,840,329；No. 4,871,549；No. 5,260,068；No. 5,260,069；5th, No. 508,040；Those described in No. 5,567,441 and No. 5,837,284.
Many other types of control release system is adapted to be used together with preparation as described herein.Such delivery system Example include, for example, the system based on polymer, such as PLA and polyglycolic acid, condensing model and polycaprolactone；For lipid The system based on non-polymer porous matrix, including sterol such as cholesterol, cholesteryl ester and aliphatic acid, or neutral fat are for example sweet Oily monoesters, diglyceride and triglycerides；Hydrogel delivery systme；Silicon rubber system；System based on peptide；Wax is coated, biology Erodible formulation, using compressed tablets of traditional binders, etc..See, e.g., Liberman et al., Pharmaceutical Dosage Forms, second edition, Vol.1, pp.209-214 (1990)；Singh et al., Encyclopedia of Pharmaceutical Technology, second edition, pp.751-753 (2002)；U.S. Patent No. 4, No. 327,725；No. 4,624,848；No. 4,968,509；No. 5,461,140；No. 5,456,923；5,516,527th Number；No. 5,622,721；No. 5,686,105；No. 5,700,410；No. 5,977,175；No. 6,465,014；With No. 6,932,983.
In some embodiments there is provided pharmaceutical preparation, its comprising compound described herein such as formula (I), (II), (IIa)、(IIaa)、(IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、 (IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、 (IIIe), the particle of the compound of (IIIee), (IIIf), (IIIff), (IV), (V) or (VI), and at least one dispersant or Suspending agent, for being administered orally to subject.Said preparation can be the powder and/or particle for suspension, and mixed with water Substantially homogeneous suspension is obtained during conjunction.
Liquid formulation dosage form for orally administering can be waterborne suspension, selected from including but not limited to pharmaceutically acceptable Aqueous oral dispersion liquid, emulsion, solution, elixir, gel and syrup.See, e.g., Singh et al., Encyclopedia Of Pharmaceutical Technology, second edition, pp.754-757 (2002).
Waterborne suspension and dispersion liquid as described herein are positively retained at such as The USP Pharmacists' Uniform state defined in Pharmacopeia (2005 editions, the 905th chapter) continues at least 4 hours.Whole group is determined by meeting The sampling method of the uniformity of compound determines uniformity.In one embodiment, the physics continuously less than 1 minute can be passed through Stirring is by waterborne suspension settling flux into unit for uniform suspension.In another embodiment, the physics continuously less than 45 seconds can be passed through Stirring is by waterborne suspension settling flux into unit for uniform suspension.In yet another embodiment, the physics continuously less than 30 seconds can be passed through Stirring is by waterborne suspension settling flux into unit for uniform suspension.In yet another embodiment, it is not necessary to stir to maintain uniform water Property dispersion liquid.
Pharmaceutical composition as described herein can include sweetener, such as, but not limited to, syrup acacia, acesulfame K, Alitame, anise, apple, Aspartame, banana, bavarian cream, berry, currant, butterscotch, calcium citrate, camphor tree Brain, caramel, cherry, cherry cream, chocolate, Chinese cassia tree, bubble gum, citrus, citrus punch (citrus punch), citrus milk Oil, cotton candy, cocoa, cola, cold cherry, cold citrus, honey element, cylamate, dextrose, eucalyptus, eugenol, fructose, water Fruit punch, ginger, enoxolone ester, radix glycyrrhizae (radix glycyrrhizae) syrup, grape, grape fruit, honey, isomaltose, lemon, bitter orange, lemon Cream, ammonium glycyrrhizinateMaltitol, mannitol, maple, cotton candy, menthol, peppermint milk Oil, mixing berry, neohesperidin DC, neotame, orange, pears, peach, peppermint, peppermint cream,Powder, cover basin Son, root juice beverage, Rum, saccharin, safrole, D-sorbite, spearmint, spearmint cream, strawberry, strawberry cream, sweetleaf Chrysanthemum, Sucralose, sucrose, saccharin sodium, saccharin, Aspartame, acesulfame potassium, mannitol, Tallin's sugar, Sucralose, D-sorbite, Switzerland's cream, Tagatose, orange, thaumatin, Tu Tifudi, vanilla, English walnut, watermelon, wild cherry, winter Any combinations of blue or green, xylitol or these flavoring ingredients, such as fennel-menthol, cherry-fennel, Chinese cassia tree-orange, cherry-meat Osmanthus, chocolate-peppermint, honey-lemon, lemon-lime, lemon-peppermint, menthol-eucalyptus, orange-cream, vanilla-peppermint with And their mixture.
In some embodiments, pharmaceutical preparation as described herein can be Self-emulsifying drug delivery system (SEDDS).Emulsion It is a kind of dispersion liquid of immiscible phase generally in droplets in the other phase.Generally, produced by violent mechanical dispersion Emulsion.SEDDS is with emulsion or microemulsion on the contrary, spontaneously forming emulsion without any outside when it is in the water added to excess Mechanical dispersion or stirring.SEDDS advantage be only need to soft mixing can be by droplet distribution in whole solution.This Outside, water or aqueous phase can be added before administration, which ensure that unstable or hydrophobic active ingredient stability.Therefore, SEDDS There is provided effective delivery system for oral and potential delivery hydrophobic active ingredient.SEDDS can provide hydrophobic active The improvement of the bioavilability of composition.The method of production self-emulsifying formulation includes but is not limited to such as U.S. Patent No. 5,858, 401, number, No. 6,667,048 and No. 6,960,563.
Exist between the additive outlined above used in aqueous liquid dispersion or suspension as described herein it is overlapping because giving Fixed additive often carries out different classifications by the different practitioners of this area, or often because of any of several difference in functionalitys Use.Therefore, additive listed above should be regarded as merely exemplary, and unrestricted be comprised in system described herein The type of additive in agent.
For intranasal preparation potential excipient include for example U.S. Patent No. 4,476,116, No. 5,116,817 and No. 6,391,452.Formulation soln in salt solution using benzylalcohol or other suitable preservatives, fluorocarbon and/or other Solubilizer or dispersant.See, e.g., Ansel, H.C. et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, sixth version (1995).Preferably, these compositions and preparation pharmaceutically may be used with suitably atoxic It is prepared by the composition of receiving.The selection of suitable carrier depends highly on desired nose formulation such as solution, suspension, emulsifiable paste or solidifying The definite property of glue.In addition to the active ingredient (s, nose formulation often contains a large amount of water.Micro other compositions such as pH regulations also may be present Agent, emulsifying agent or dispersant, preservative, surfactant, gelling agent or buffer and other stabilizers and solubilizer.It is preferred that Ground, nose formulation should be isotonic with nasal discharge.
For being applied by sucking, compound as described herein can be the form as aerosol, mist agent or pulvis. By using suitable propellant such as dicholorodifluoromethane, Arcton 11, dichlorotetra-fluoroethane, carbon dioxide or other conjunctions Suitable gas, since self-pressurization packaging or the aerosol spray form of sprayer easily deliver drug regimen as described herein Thing.In the case of a pressurized aerosol, dosage unit can be determined by providing for delivering the valve of metered amount.Such as only make For example, capsule and cylinder casket for inhalator or the gelatin of insufflator can be formulated containing compound described herein and suitable The mixture of powders of powder base such as lactose or starch.
Can be applied containing formulation using several formulations comprising compound described herein, said preparation includes but is not limited to U.S. State's patent No. 4,229,447, No. 4,596,795, No. 4,755,386 and No. 5,739,136.In addition, described herein Can further include bioerodible (hydrolyzable) polymer support containing oral dosage form, the carrier is additionally operable to adhere to the formulation To oral mucosa.It is prepared for containing oral dosage form so as to gradually corrosion within a predetermined period of time, wherein substantially providing compound always Delivering.Buccal medicine delivery avoids oral drugs and applies run into shortcoming, for example, slow-absorbing, activating agent are stored in First cross in fluid degradation and/or liver in intestines and stomach inactivates.For bioerodible (hydrolyzable) polymer support, Any such carrier actually can be used, if desired drug release characteristics are without prejudice, and the carrier and this paper institutes Any other component that may be present is compatible in the compound stated and buccal dosage unit.Generally, polymer support includes viscous It is attached to hydrophily (water-soluble and water-swellable) polymer of the wet structure of buccal mucous membrane.Polymer support useful herein Example include acrylate copolymer and copolymer, be for example referred to as " carbomer " (It can be from B.F.Goodrich is obtained, and is a kind of such polymer) those.Other components can also be mixed as described herein buccal In formulation, including but not limited to disintegrant, diluent, adhesive, lubricant, flavor enhancement, colouring agent, preservative etc..For containing Clothes or sublingual administration, composition can take the form of the tablet prepared in a usual manner, lozenge or gel.
Percutaneous preparation as described herein can be applied using a variety of devices, be included but is not limited to, U.S. Patent No. 3,598,122 Number, No. 3,598,123, No. 3,710,795, No. 3,731,683, No. 3,742,951, No. 3,814,097, the 3rd, No. 921,636, No. 3,972,995, No. 3,993,072, No. 3,993,073, No. 3,996,934, the 4,031,894th Number, No. 4,060,084, No. 4,069,307, No. 4,077,407, No. 4,201,211, No. 4,230,105, the 4th, No. 292,299, No. 4,292,303, No. 5,336,168, No. 5,665,378, No. 5,837,280, the 5,869,090th Number, No. 6,923,983, No. 6,929,801 and No. 6,946,144.
Transdermal as described herein can mix some pharmaceutically acceptable excipient conventional in the art.At one In embodiment, percutaneous preparation as described herein includes at least three kinds components：(1) formula (I), (II), (IIa), (IIaa), (IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、 (IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、 (IIIf), the preparation of the compound of (IIIff), (IV), (V) or (VI)；(2) penetration enhancer；(3) aqueous adjuvants.In addition, Percutaneous preparation can include other components, such as, but not limited to, gelling agent, emulsifiable paste and ointment base bottom, etc..In some embodiments In, percutaneous preparation can further comprise weaving or nonwoven interlining bottom material, to strengthen absorption and prevent percutaneous preparation from skin Remove.In other embodiments, percutaneous preparation as described herein can maintain saturation or over-saturation state, to promote into skin It is scattered.
Transdermal delivery device and dermal delivery paster can be used suitable for the preparation of applied dermally compound described herein, and Can for lipophilicity emulsion or buffering aqueous solution, dissolve and/or be dispersed in polymer or adhesive in.Such paster The continuous delivering of medicine agent, pulse can be configured to deliver or deliver on demand.Further, the warp of compound described herein Skin delivering can be realized by means such as iontophoretic patch.In addition, transdermal patch can provide the control of compound described herein Delivering.The speed of absorption can be slowed down by using rate controlling membranes or by catching compound to be trapped in polymeric matrix or gel Rate.On the contrary, absorption enhancer increase can be used to absorb.Absorption enhancer or carrier can include absorbable pharmaceutically acceptable Solvent is to help through skin.For example, transcutaneous device is the form of bandage, its comprising substrate film, contain compound and optional The reservoir of carrier, optional speed control barrier layer, within the period of extension under control and predetermined speed to place The main dermal delivery compound, and for the device to be fixed on to the means of skin.
Physiologically acceptable aseptic aqueous solution can be included suitable for the preparation of intramuscular, subcutaneous or intravenous injection Or non-aqueous solution, dispersion liquid, suspension or emulsion, and for being reconstructed into the aseptic powder of sterile injectable solution or dispersion liquid End.Suitable aqueous and non-aqueous carrier, diluent, the example of solvent or medium include water, ethanol, polyalcohol (propane diols, Polyethylene glycol, glycerine, rilanit special etc.), their suitable mixture, vegetable oil (such as olive oil) and injectable is organic Ester such as ethyl oleate.For example, can be big by the particle needed for maintenance such as lecithin, in the case of dispersion liquid by using being coated It is small, and maintain by using surfactant appropriate mobility.It can also contain addition suitable for hypodermic preparation Agent such as preservative, wetting agent, emulsifying agent and dispersant.Such as p-hydroxybenzoate, methaform, phenol, sorbic acid can be passed through Ensure to prevent microorganism from growing etc. a variety of antiseptics and antifungal agent.It can also expect to include isotonic agent, such as sugar, sodium chloride. It can realize that the extension of injectable drug form absorbs by using the medicament such as aluminum monostearate and gelatin of delayed absorption.
For intravenous injection, compound described herein can be prepared in aqueous solution, preferably prepared in physiological compatible Buffer solution such as Hank solution, Ringer solution or normal saline buffer solution in.For mucosal administration, in the formulation using suitable Together in the bleeding agent of barrier to be infiltrated.Such bleeding agent is usually recognized by this area.For other parenteral injections, Suitable preparation can include aqueous or non-aqueous solution, buffer solution or excipient preferably with physiological compatible.It is such to assign Shape agent is usually recognized by this area.
Parenteral injection can relate to bolus infusion or continuous infusion.Preparation for injection can exist with unit dosage forms, For example, in the ampoule or multi-dose container added with preservative.Pharmaceutical composition as described herein can be to be suitable as nothing Bacterium suspension, solution or the emulsion in oiliness or aqueous vehicles carry out the form of parenteral injection, and can contain allotment Agent, such as suspending agent, stabilizer and/or dispersant.Pharmaceutical preparation for parenteral administration is included as the activation of water-molten form The aqueous solution of compound.In addition, the suspension of reactive compound can be prepared into suitable oily injection suspensions.Suitable lipophilic Property solvent or medium include fat oil, such as sesame oil or Acrawax, such as ethyl oleate or triglycerides, or lipid Body.Water injection suspension liquid can be containing the material of suspension viscosity be increased, and such as sodium carboxymethylcellulose, D-sorbite or Portugal gather Sugar.Optionally, the suspension also containing suitable stabilizer or can increase the medicament of the compound solubility, high to allow to prepare Spend the solution of concentration.Alternatively, active component can be powder type, for preceding with for example sterile nothing of suitable medium in use Pyrogen water restores.
In certain embodiments, the delivery system of medical compounds, such as, liposome and emulsion can be used. In some embodiments, provided herein is composition also include mucoadhesive polymers, its be selected from such as carboxymethyl cellulose, card Ripple nurse (acrylate copolymer), poly- (methyl methacrylate), polyacrylamide, polycarbophil, acrylic acid/butyl acrylate are common Polymers, sodium alginate and glucan.
In some embodiments, compound as described herein can local application and be formulated into it is a variety of can local application Composition, such as solution, suspension, lotion, gel, paste, medicine rod, balm, emulsifiable paste or ointment.Such medical compounds can Contain solubilizer, stabilizer, tension-elevating agent, buffer and preservative.
Compound described herein can also be formulated as rectal compositions, such as enema, rectal gel, rectal foams, rectum gas Mist agent, suppository, jelly suppository or enema,retention, said composition contain conventional suppository bases such as cocoa butter or other glyceride with And synthetic polymer such as polyvinylpyrrolidone, PEG etc..In the suppository form of composition, low melt wax is melted first, such as But it is not limited to the fatty glyceride mixt optionally combined with cocoa butter.
Generally, medicament such as formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、 (IIIcc), the compound of (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) with Be effectively improved or prevention disease or condition symptoms development amount (that is, therapeutically effective amount) apply.Therefore, therapeutically effective amount can be Can at least partly prevent or reverse disease or illness amount.Dosage needed for obtaining effective dose can be according to medicament, preparation, disease Or illness, and medicament be applied to individual and change.
The determination of effective dose may also refer to such external test, wherein by the pharmacy application of various dose into cultivating Cell, and the drug concentration for being effectively improved some or all symptoms is determined, to calculate concentration required in vivo.Effective dose Animal In vivo study can be also based on.
Medicament can be before the symptom of disease or illness occurs, while and applying afterwards.In some embodiments, medicament The subject of the family history with disease or illness is applied to, or with the tendentious phenotype that may indicate that disease or illness Subject, or with make subject tend to be attacked by a disease or illness phenotype subject.
Specific delivery system may depend on many factors, include the target and the approach of administration of such as purpose, for example, office Apply or systemic administration in portion.The target of delivering can be the specific cells for causing or causing disease or illness.For example, target cell can be Cause resident cell or the infiltrating cells in the nervous system of nerve, nervus retrogression or demyelinating disease or illness.Medicine The administration of agent can be directed to the subgroup of one or more cell types or cell type by art recognized methods.For example, Medicament can be mutually coupled with antibody, the part of cell surface receptor or toxin, or can be comprised in optionally internalization into cell Particle (for example, liposome, or the virus that virus receptor is combined with some cell type specificities, or deleted virus nucleic acid Virion) in, or can local application.
Medication and therapeutic scheme
Compound as described herein can be used for preparing and be used to adjusting TRPV1 or will be at least partly from TRPV1 for treating The disease or the medicine of situation benefited in regulation.In addition, any this paper institutes for treating the subject for needing this kind for the treatment of The method for stating disease or situation contains at least one compound described herein including being applied with therapeutically effective amount to the subject Or the pharmaceutical composition of its pharmaceutically acceptable salt or pharmaceutically acceptable solvate or hydrate.
Composition containing compound described herein, which can be applied, is used for prophylactic treatment and/or therapeutic treatment.In treatment Property application in, said composition be applied to suffered from the amount of symptom for being enough to cure or at least partly prevent disease or situation The patient of the disease or situation.Effective for the purposes amount by depending on the seriousness and process of the disease or situation, previously Therapy, the health status of patient, body weight, and the response to medicine, and treating physician judgement.
In prophylactic use, the composition containing compound described herein, which is applied to, doubtful to be suffered from or there is specific disease The patient of the risk of disease, illness or situation.Such amount is defined as " prevention effective dose or prevention effective dose ".In the purposes In, accurately amount also depends on health status, body weight of patient etc..When for patient, the effective dose for the purposes will take Certainly in the seriousness and process of the disease, illness or situation, previous therapies, patient health status, and the response to medicine, with And the judgement for the treatment of physician.
According to the judgement of doctor, the administration of compound chronic can be applied, i.e., the period persistently extended, including patient vitals The whole duration, to improve or otherwise control or limit the symptom of patient disease or situation.
According to the judgement of doctor, the administration of compound can continuously be given；Or, applying the dosage of medicine can temporarily be reduced Or temporarily cease a period of time (that is, " drug holiday ").The length of drug holiday can change between 2 days to 1 year, only as reality Example, including 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days or 365 days.Agent during medicine holiday Amount reduction can be about 10% to about 100%, only as example, including about 10%, about 15%, about 20%, about 25%, about 30%, About 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, About 90%, about 95% or about 100%.
Once the situation of patient improves, as needed using maintenance dose.Then, according to symptom by applied dose Frequency or the two be reduced to and retain improved disease, the level of symptom or situation.However, in any recurrence of symptom, suffering from Person may need long-term Intermittent treatment.
Will be according to such as specific compound, disease or situation and its tight by the amount for giving medicament corresponding with such amount Principal characteristic, need the factor such as characteristic (for example, weight) of the subject or host treated and change, but also can be according to the spy of the case Condition of pledging love determines in the art recognized manner, including, for example, the particular compound applied, route of administration, the shape treated Condition and the subject or host treated.However, the dosage used typically for Adult Treatment will be often daily about In the range of 0.001mg to about 5000mg daily, in some embodiments, in about 1mg daily to about 1500mg daily model In enclosing.Desired dosage easily can be present in single dosage, or as (or within shorter period) simultaneously apply or The fractionated dose for applying (for example, twice daily, three times, four times or more sub- dosage) at suitable intervals is present.
Pharmaceutical composition as described herein can exist with the unit dosage forms of the single administration suitable for correct dose.In list In the formulation of position, preparation is divided into the unit dose containing proper amount of one or more compounds.Unit dose can be containing from Dissipate the form of the packaging of volume preparation.Non-limiting examples are the tablet or capsule of packaging, and the pulvis in bottle or ampoule.Can Aqueous suspension composition is packaged in the not single-dose containers of Reclosable.Or, many of Reclosable can be used Dose container, often includes preservative in this case in composition.Only as example, the preparation for parenteral injection can be with Exist with the unit dosage forms for including but is not limited to ampoule, or exist with the multi-dose container added with preservative.
The suitable daily dosage of compound described herein is about 0.001mg/kg to about 30mg/kg.In an embodiment In, daily dosage is about 0.01mg/kg to about 10mg/kg.It is specified every in the larger mammal of including but not limited to people Daily dose is in the range of about 0.1mg to about 1000mg, and it easily (is included but is not limited to every with single-dose or divided doses Day at most four times) or the administration in the form of extending release.Suitable unit dosage forms for orally administering include about 1 to about 500mg Active component.In one embodiment, unit dose is about 1mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg, about 200mg, about 250mg, about 400mg or about 500mg.Aforementioned range is only suggestiveness, because being controlled on individual The variables number for the treatment of scheme is very big, and is not uncommon for the sizable deviation of these recommendations.These dosage can be according to a variety of Variable and change, be not limited to compound used therefor disease active, to be treated or situation, method of application, individual subjects will Seek, treat the seriousness of disease or situation, and practitioner judgement.
The toxicity and treatment effect of these therapeutic schemes can pass through the standard drug journey in cell culture or experimental animal Sequence determines, including but not limited to LD50(dosage lethal to 50% colony) and ED50(therapeutically effective dose in 50% colony Amount) measure.Dose ratio between toxicity and therapeutic effect is therapeutic index and is represented by LD50With ED50The ratio between.Show The compound of high therapeutic index is preferred.The data obtained from cell culture measure and zooscopy can be used for being formulated for The dosage of people.The dosage of these compounds is preferably fallen in including the ED with minimum toxicity50Circulation composition in the range of.The dosage Can within the range it be changed according to the dosage form and used route of administration that are used.
Therapeutic alliance
Formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId), (IIdd), (IIe), (IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、 (IIId), compound of (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) and combinations thereof It can also be used with the combination with other therapeutic agents selected because of its therapeutic value for situation to be treated.Generally, it is as described herein Composition, and using conjoint therapy embodiment in other medicaments need not be applied in same pharmaceutical composition, and It must may be applied due to different Physical and chemical characteristics by different approaches.In the conceived case, with same Pharmaceutical composition is complete within the knowledge of clinician come the determination of the mode and the appropriateness of administration applied.Initial application can Carried out according to art-recognized existing plan, the effect then arrived according to the observation, can be changed by clinician method of application and Time of application.
In some cases, it is probably suitable at least one compound described herein to be administered in combination with another therapeutic agent 's.Only as example, if patient receive a kind of compounds herein for example formula (I), (II), (IIa), (IIaa), (IIb), (IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、 (IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、(IIIf)、 (IIIff) a kind of side effect, undergone when (IV), (V) or (VI) compound is nausea, then by anti-nausea agent and initial treatment It is probably suitable that agent, which is administered in combination,.Or, only as example, a kind of compound described herein can be strengthened by applying adjuvant Treatment validity (that is, the adjuvant itself may have small treatment benefit, but to patient's when being combined with another therapeutic agent Overall therapeutic benefit is strengthened).Or, only as example, can by by a kind of compound as described herein with equally having Another therapeutic agent for the treatment of benefit is applied to increase the benefit that patient is undergone at (it also includes therapeutic scheme) together.In any feelings Under condition, regardless of the disease, symptom or situation treated, the overall benefit that patient is undergone may simply be two kinds of therapeutic agents It is cumulative, or patient can undergo synergistic benefits.
In some cases, being combined with another therapeutic agent is combined with local anesthetic.As used herein, term " office Anesthetic " refers to the medicine for providing mono-anesthesia or pain relief.The local anesthetic that can be applied in combination with the present invention shows Example property example includes：Bupivacaine, chirocaine, Ropivacaine, cincaine, procaine, chloroprocanine, propylamine card Cause, mepivacaine, Etidocaine, totokaine and lidocaine.
In some cases, being combined with another therapeutic agent is combined with vasoconstrictor.Useful vasoconstrictor is office Those vessel retractions that portion's effect is flowed with limit blood and is thus maintained at the medicine injected in the region that it is applied Agent.This, which has, significantly reduces the effect of general toxicity.It is preferred that vasoconstrictor be that act on alpha-2 adrenoceptor A bit, such as adrenaline and phyenlephrinium.
In some cases, being combined with another therapeutic agent is combined with glucocorticoid.Glucocorticoid is selected from ground plug rice Pine, cortisone, hydrocortisone, metacortandracin, beclomethasone, betamethasone, flunisolide, meprednisone, paramethasone, bold and vigorous Buddhist nun Song Long, fluoxyprednisolone, alclometasone, Amcinonide, clobetasol, fludrocortison, acetic acid diflorasone, FA, fluorine rice Dragon, fludroxycortide, halcinonidedcorten, medrysone, Mometasone and acceptable salt and their mixture.
In some embodiments, formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、 (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) Compound, or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate are combined with local anesthetic and made With.
In some embodiments, formula (I), (II), (IIa), (IIaa), (IIb), (IIbb), (IIc), (IIcc), (IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、(IIIa)、(IIIaa)、(IIIb)、(IIIbb)、 (IIIc), (IIIcc), (IIId), (IIIdd), (IIIe), (IIIee), (IIIf), (IIIff), (IV), (V) or (VI) Compound, or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate and non-opioid analgesic agents group Conjunction is used.
Compound used therefor it is specifically chosen by the diagnosis depending on attending doctor and its judgement to status of patient and suitable When therapeutic scheme.The compound can be applied (for example, being administered simultaneously, substantially simultaneously applying or in same therapeutic scheme parallel It is interior to apply) or order administration, this depends on the reality of disease, the property of illness or situation, the situation of patient and compound used therefor Selection.After the treated disease of evaluation and status of patient, every kind of therapeutic agent is applied in the determination of order of administration and therapeutic scheme Number of repetition completely in the knowledge of doctor.
When medicine is used for therapeutic combination, treatment effective dose may change.Described in document for experimentally true Surely the method for being used for the medicine of combined treatment and the treatment effective dose of other reagents.For example, being generally described in document Using sinusoidal administration, that is, provide frequent, more relatively low-dose to minimize toxic side effect.Therapeutic alliance further comprises not The periodic therapeutic for starting with the time and stopping, to aid in the clinical management of patient.
For conjoint therapy as described herein, the dosage of compound, which is co-administered, to depend on what is used in the nature of things The type of composite medicine, the specific medicine used, the disease treated or situation, etc..In addition, when biological with one or more Activating agent be co-administered when, provided herein is compound can be administered simultaneously or sequentially with the bioactivator.If order is applied, The proper order that then protein and the bioactivator are administered in combination attending doctor for decision.
Under any circumstance, a variety of therapeutic agents (one of which be formula as described herein (I), (II), (IIa), (IIaa), (IIb)、(IIbb)、(IIc)、(IIcc)、(IId)、(IIdd)、(IIe)、(IIee)、(IIf)、(IIff)、(III)、 (IIIa)、(IIIaa)、(IIIb)、(IIIbb)、(IIIc)、(IIIcc)、(IIId)、(IIIdd)、(IIIe)、(IIIee)、 (IIIf), (IIIff), (IV), (V) or (VI) compound) it can be applied or be even administered simultaneously with random order.If simultaneously Using then a variety of therapeutic agents can be provided (only as an example, being used as single injection using single unified form or diversified forms Or individually injection twice).One kind of therapeutic agent can be given with multiple dosage, or both can with multiple dosage to Give.If not being administered simultaneously, then the selection of time between multiple dosage can change more than zero circle to less than between surrounding.This Outside, combined method, composition and preparation are not limited to the use of only two kinds medicaments；The use of a variety of therapeutic combinations is also expected 's.
It should be understood that the dosage side for treating, preventing or improving the situation for seeking to alleviate can be changed according to many factors Case.These factors include the subject illness or situation suffered from, and subject age, body weight, sex, diet and medical treatment Situation.Therefore, the actual dosage used can be widely varied, therefore can deviate dosage regimen as described herein.
The medicament for constituting conjoint therapy disclosed herein can be combination dosage forms or the independent formulation for being administered simultaneously substantially. Constituting the medicament of conjoint therapy also can sequentially apply, and wherein therapeutic compounds is by needing the scheme that two steps are applied to apply.This two Step application program can need the order of activating agent to apply or the individually interval administration of activating agent.Time between multiple step of applying Duan Kewei a few minutes to a few hours, this depends on the property of every kind of medicament, the effect of such as medicament, solubility, bioavilability, blood Starch half-life period and kinetic spectrum.The day-night change of concentration of target molecules may further determine that optimal dosing interval.
In addition, compound described herein can also be used with that can provide the suite of extra or synergistic benefits for patient.Only Example is used as, it is contemplated that patient will have found therapeutic and/or preventative benefit in method described herein, wherein will be disclosed herein The pharmaceutical composition of compound and/or pharmaceutical composition with combination with other therapeutic agents are combined with heredity test, to determine this Body whether be the known mutator related to some diseases or situation carrier.
Compound as described herein and conjoint therapy can be applied before, during or after disease or situation occur, and It can change using the selection of time of the composition containing compound.Thus, for example, compound can be used as prophylactic, and it can connect It is continuous be applied to tend to develop have troubles or the subject of disease is to prevent the generation of disease or situation.The compound and composition Subject can be applied to during paresthesia epilepsy or subject is applied to as quickly as possible after breaking out.The administration of compound can be Carried out in initial 48 hours of paresthesia epilepsy, preferably in initial 48 hours of paresthesia epilepsy, more preferably in paresthesia epilepsy most In first 6 hours, most preferably in 3 hours of paresthesia epilepsy.Initial application can be such as quiet via any feasible approach Injection, bolus infusion in arteries and veins, through about 5 minutes to about 5 hours infusion, pill, capsule, transdermal patch, delivery services etc., or it Combination.Preferably, detect suspect disease or situation breaking-out after compound is applied when feasible as early as possible, and apply With the time span needed for the continued treatment disease, such as, 1 day to about 3 months.The treatment length of each subject is variable Change, and the length can be determined using known standard.For example, compound or the preparation containing the compound can be applied at least 2 weeks, preferably from about 1 month to about 5 years.
Medicine box/product
In order to which for treatment use as described herein, there is also described herein medicine box and product.Such medicine box can include quilt Subregion is to receive the carrier, packaging or container of one or more containers (such as bottle, pipe etc.), and each container, which is included, is used for this The single element of one of literary methods described.Suitable container includes such as bottle, bottle, syringe and test tube.The container can be by Various materials such as glass or plastics are formed.
For example, the container can include one or more compounds as described herein, optionally in the composition or with such as Literary disclosed another pharmaceutical agent combinations.Optionally, the container has sterile access port (for example, the container can be intravenous solution bag Or with can be by the bottle of the plug of hypodermic injection needle-penetration).Optionally, such medicine box, which is included, has identification description or label Compound, or the specification related to its purposes in methods described herein.
Typically, medicine box can often include one or more extra containers, and each container is respectively provided with from using described herein One kind of the business and the desired multiple material of user's position (reagent and/or device as being optionally in conc forms) of compound Or it is a variety of.The non-limiting examples of this kind of material include but is not limited to buffer solution, diluent, filter, syringe needle, syringe；Carry Body, packaging, container, bottle and/or the pipe label and/or operation instructions of listing content, and with operation instruction Package insert.Generally it will also include a group profile.
Label can be on container or associated with container.When the letter, numeral or the attachment of other characters, the molding that form label Or etch into container it is middle in itself when, label can be on container；When label, which is present in, also to be accommodated in the vessel or carrier of container, mark Label can be associated with the container, such as packaging page.Label, which may be used to indicate content, will be used for specific treatment use.Mark Label may further indicate that the guide for use of content, the guide for use such as in methods described herein.
Embodiment
These embodiments are provided for illustration purposes only, not limit provided herein is claim scope.For The parent material and reagent for synthesizing compound described herein can be synthesis or can be from such as, but not limited to Sigma-Aldrich Corp., Acros Organics, Fluka and Fisher Scientific commercial source is obtained.
Synthetic example
Embodiment 1：(E) -2- methoxyl groups -4- ((8- methyl nonyl- 6- acrylamides base) methyl) phenyl (2- amino-ethyls) (methyl) The synthesis of carbamate (1)
Compound A-1 preparation
Capsaicine (200mg, 0.65mmol, 1.0eq) is dissolved in DCM (10mL), then addition 4- nitrobenzophenone chlorine Formic acid esters (138mg, 0.68mmol, 1.05eq) and DIPEA (346mL, 1.95mmol, 3.0eq).Reaction is allowed to stir at room temperature Mix 4h.HOAt (97mg, 0.715mmol, 1.1eq) and (2- (methylamino) ethyl) tertiary fourth of carbamic acid is added into the reaction Ester (135mg, 0.78mmol, 1.2eq).Reaction is allowed to be stirred at room temperature (18h).Next, with 1N HCl (2X15mL), NaHCO3Saturated aqueous solution (5X15mL) and last saturation halogen water (15mL) wash the reaction.Remove organic layer, through MgSO4 Dry, filter and be concentrated under vacuum to obtain A-1.The substance migration is without being further purified.
The preparation of compound 1
To thick A-1 (from reactant mixture achieved above) addition DCM (3mL) and trifluoroacetic acid (1mL).Allow reaction 1h is stirred at room temperature in mixture.1 is concentrated and is dissolved in next, will react:1HOAc:H2In O (10mL).Pass through preparative Reversed-phase HPLC (Agilent Prep C-18 posts, mobile phase A：100% water, 0.1%TFA；Mobile phase B：100%ACN, 0.1% TFA；Through 20min20% to 70%B gradient elutions) purifying crude mixture, with the tfa salt for the compound 1 for obtaining white solid (188.1mg, 0.36mmol, through two step yields for 55.6%).(the chemical formulas of LC-MS [M+H] 406.6：C22H35N3O4+ H, is calculated Value：406.3).
Embodiment 2：(E) -2- methoxyl groups -4- ((8- methyl nonyl- 6- acrylamides base) methyl) phenyl methyl (2- methylaminos) second Base) carbamate (2) synthesis
Except substituting (2- (methylamino) ethyl) amino with methyl (2- (methylamino) ethyl) t-butyl carbamate Outside t-butyl formate, the preparation of compound 2 follows the synthetic method of embodiment 1.This method produces into the title of white solid The tfa salt (192.7mg, 0.36mmol, 55.4% yield) of compound.(the chemical formulas of LC-MS [M+H] 420.7：C23H37N3O4+H, Calculated value：420.2).
Embodiment 3：(E) -2- methoxyl groups -4- ((8- methyl nonyl- 6- acrylamides base) methyl) phenyl 2- (amino-ethyl) piperidines -1- The synthesis of carboxylate (3)
Except substituting (2- (methylamino) ethyl) tertiary fourth of carbamic acid with (piperidin-2-yl methyl) t-butyl carbamate Outside ester, the preparation of compound 3 follows the synthetic method of embodiment 1.This method produces into the title compound of white solid Tfa salt (222.4mg, 0.39mmol, 61.1% yield).(the chemical formulas of LC-MS [M+H] 446.7：C25H39N3O4+ H, calculated value： 446.3)。
Embodiment 4：(E) -2- methoxyl groups -4- ((8- methyl nonyl- 6- acrylamides base) methyl) phenyl 2- (amino-ethyl) pyrrolidines - The synthesis of 1- carboxylates (4)
Except substituting (2- (methylamino) ethyl) carbamic acid uncle with (pyrrolidin-2-yl methyl) t-butyl carbamate Outside butyl ester, the preparation of compound 4 follows the synthetic method of embodiment 1.This method produces into the title compound of white solid Tfa salt (202.1mg, 0.37mmol, 57.0% yield).(the chemical formulas of LC-MS [M+H] 432.7：C24H37N3O4+ H, is calculated Value：432.2).
Embodiment 5：(E) double (2- amino-ethyls) amino of -2- methoxyl groups -4- ((8- methyl nonyl- 6- acrylamides base) methyl) phenyl The synthesis of formic acid esters (5)
Except substituting (2- (methylamino) with (azane diyl is double (ethane -2,1- diyls)) diamino acid di tert butyl carbonate Ethyl) outside t-butyl carbamate, the preparation of compound 5 follows the synthetic method of embodiment 1.It is solid that this method produces into white The tfa salt (217.0mg, 0.33mmol, 50.4% yield) of the title compound of body.(the chemical formulas of LC-MS [M+H] 435.7： C23H38N3O4+ H, calculated value：435.2).
Embodiment 6：(E) -2- methoxyl groups -4- ((8- methyl nonyl- 6- acrylamides base) methyl) phenyl (3- aminopropyls) (methyl) The synthesis of carbamate (6)
Except substituting (2- (methylamino) ethyl) carbamic acid with (3- (methylamino) propyl group) t-butyl carbamate Outside the tert-butyl ester, the preparation of compound 6 follows the synthetic method of embodiment 1.This method produces into the title compound of white solid The tfa salt (149.6mg, 0.28mmol, 43.0% yield) of thing.(the chemical formulas of LC-MS [M+H] 420.7：C23H37N3O4+ H, is calculated Value：420.5).
Embodiment 7：(E) -2- methoxyl groups -4- ((8- methyl nonyl- 6- acrylamides base) methyl) phenyl 2- (methylamino) methyl) piperazine The synthesis of pyridine -1- carboxylates (7)
Except substituting (2- (methylamino) ethyl) carbamic acid with methyl (piperidin-2-yl methyl) t-butyl carbamate Outside the tert-butyl ester, the preparation of compound 7 follows the synthetic method of embodiment 1.This method produces into the title compound of white solid The tfa salt (183.2mg, 0.32mmol, 49.2% yield) of thing.(the chemical formulas of LC-MS [M+H] 460.7：C23H37N3O4+ H, is calculated Value：460.3).
Embodiment 8：(E) -2- methoxyl groups -4- ((8- methyl nonyl- 6- acrylamides base) methyl) phenylpiperazine -1- carboxylates (8) Synthesis
In addition to substituting (2- (methylamino) ethyl) t-butyl carbamate with piperazine -1- carboxylic acid tert-butyl esters, chemical combination The preparation of thing 8 follows the synthetic method of embodiment 1.This method produces into the tfa salt of the title compound of white solid (186.4mg, 0.35mmol, 53.9% yield).(the chemical formulas of LC-MS [M+H] 418.4：C23H37N3O4+ H, calculated value： 418.3)。
Embodiment 9：(E) -2- methoxyl groups -4- ((8- methyl nonyl- 6- acrylamides base) methyl) phenylpiperazine -1- carboxylates (9) Synthesis
Except substituting (2- (methylamino) ethyl) with methyl ((4- methyl piperazine -2- bases) methyl) t-butyl carbamate Outside t-butyl carbamate, compound 9 follows the synthetic method of embodiment 1 to prepare.
External test
Embodiment 10：Solubility test
To determine the water solubility of compound described herein, by the HCl salt of following compound in DI water 50 or 100mg/mL It is lower to incubate, then vibrate 24 hours.Then, by solution centrifugal and the undissolved material of visual inspection.In all cases all not It was observed that undissolved material.
a Supernatant is diluted to be quantified with 3 calibration curves.
Compared to water solubility (about 0.064mg/mL) of the capsaicine in water, the hydrochlorides of these compounds shows water-soluble Property is greatly improved.In general, this represents that water solubility improves more than 1560 times (embodiments 1 from parent compound capsaicine With 2) and 780 times (embodiment 3).
These results are represented when preferred aqueous solution is used to deliver, using compound phase described herein for capsaicine Significant advantage.For example, in the case where extra solubilizer is not used, the aqueous solution of per unit volume can deliver significantly more The material of compound described herein (compared to capsaicine).
Embodiment 11：(pH stability) is determined in vitro
Confirm parent drug (for example, capsaicine) from described herein by the synthesis and stability test of several compounds The release of compound.These compounds are the examples that pH activates prodrug, so as to when exposed to specific pH, determine intramolecular cyclization The half-life period of release reaction.As previously described, intramolecular cyclization release reaction causes as parent drug release is with formation Ring-type urea.
By compound specified buffer solution/Biomedia (from Sigma-Aldrich, St.Louis, MO, what USA was obtainedCatalog number (Cat.No.) T1503) middle incubation.Reaction is carried out at room temperature or 37 DEG C.Sample is collected in particular point in time, by its turn Move to stop cyclisation release reaction in 0.1%HCl solution, and analyze by HPLC formation and the initial compounds of capsaicine Consumption.
Condition：A) pH=about 7.4 (the aqueous tris buffer solutions of 0.3M), 20 DEG C；B) (the aqueous tris bufferings of 1.0M of pH=about 7.4 Liquid), 37 DEG C；
N/A：Through 2 weeks, embodiment 8 did not showed any measurable conversion to capsaicine.
Although there is structural similarity between institute's test compound, institute's test compound group shows widely varied ring Change speed.Intramolecular cyclization discharges scope of the half-life period result in several minutes (embodiment 3,5 and 7) to a few days (embodiment 4 and 6) It is interior.These results show the rapid delivery or the useful compound group of delay delivering to parent drug.
Other common composition/preparations that can be used in the buffer solution for testing the cyclisation release of compound described herein Including but not limited to：N- (2- acetylaminos)-Tau, N- (2- acetylaminos) iminodiacetic acid, 2- amino -2- Methyl-1,3-propanediol, bicarbonate, N, double (2- ethoxys) glycine of N-, double (2- ethoxys) amino -2- (the hydroxyl first of 2- Base) -1,3- propane diols, 3- (Cyclohexylamino) -1- propane sulfonic acid, 2- (Cyclohexylamino) ethyl sulfonic acid, carbonate, citrate, 4- (2- ethoxys) -1- piperazines propane sulfonic acid, glycinate, glycyl-glycine salt, 4- (2- ethoxys) piperazine -1- ethyl sulfonic acids, [(2- hydroxyls -1,1- is double by 4- morpholino b acids, 4- N-morpholinyls, the ethyl sulfonic acid of 1,4- piperazines two, phosphate, tartrate, 2- (methylol) ethyl) amino] ethyl sulfonic acid, three (2- ethoxys) amine, and edta salt.
Embodiment 12：External combination mensuration
Due to the intrinsic pH unstability of compound described herein, compound 1-7 is in half maximum suppression concentration (IC50) determine In test will be involved because of formation of the parent drug (capsaicine) under condition determination (pH=about 7-8).However, containing change Learn related amino-amino carbamate moiety but can not carry out in chemistry intramolecular cyclization-release compound 8 show with The minimum combination of TRPV acceptors, its IC50>100uM (23% suppresses@100uM).
Eurofins, Panlabs/Cerep determine title：Class Vanillin, catalog number (Cat.No.)：286810；Parallel control：Resin gliotoxin =0.16nM, historical control：Capsaicine=3.1 μM, resin gliotoxin=0.46nM.Because compound 8 is to vanilloid receptor It there is no activity and Capsaicinoids be not to be regarded as according to definition, therefore compound as described herein (for example, Compound 1-7) similar binding property will be shown and will not also be classified as Capsaicinoids.
In addition, structure-activity relationship (SAR) data from many parts of bibliography are it has been proved that capsaicine and resin gliotoxin The substitution of phenol position produce the activity of TRPV1 acceptors is greatly reduced compound (Huang, et al. Current Medicinal Chemistry,2013,20,2661-2672)。
Embodiment 13：Pharmacokinetics measure-IM is applied to the blood plasma time course of test compound after rat
IM is administered：Test compound is dissolved in salt solution, and via intramuscular administration to male Sprague- Dawley rats.Capsaicine is used as positive control, and test compound is administered in the form of HCl salt.Test compound with Mg/kg body weight is administered and matched by a mole correction with the amount with the capsaicine being administered.Particular point in time (0.5h, 1h, 2h, 4h, 8h, 12h, 24h, 36h, 72h), extract blood sample, by its in ACN (contain 0.5% formic acid) quenching, Centrifuge and be stored at -80 DEG C until analysis under 14000rp and rt.Via LC/MS/MS by sample amounts.Can report capsaicine, The plasma concentration of prodrug and produced ring-type urea.
Embodiment and embodiment being merely to illustrate property purpose as described herein, and in certain embodiments, the disclosure A variety of modifications or change will be included in the scope and scope of the following claims of content.

Claims (64)

1. the compound with formula (I) structure：
Wherein：
Y is phenols TRPV1 activators, and the hydrogen atom of wherein phenolic hydroxy group is bonded to-C (O)-X- (C (R1)(R2))n- Z's Covalent bond is replaced；
X is-C (R1)(R2)-、-O-、-N(R5)-or-S-；
N is 1 to 10 integer；
Z is-NR3R4Or-CO2H；
R5For hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, and each R1And R2It is each independently Hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted acyl group, or adjacent carbon atom On two R1Or R2The carbon atom that group is attached together with them forms substituted or unsubstituted group of naphthene base, Huo Zhexiang R on adjacent atom1And R5The atom that group is attached together with them forms substituted or unsubstituted heterocycloalkyl；And
R3And R4It is each independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl；
Or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or hydrate.
2. compound as claimed in claim 1, wherein Y areR6Independently selected from hydrogen, halogen ,-CN ,- NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkane Base)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkane Epoxide, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, aryl are sub- Sulfone, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For substituted or unsubstituted alkyl.
3. compound as claimed in claim 2, wherein R7For unsubstituted alkyl or it is selected from one or more groups of the following group Substituted alkyl：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (= O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, Cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, virtue Base is thio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.
4. the compound as any one of claim 1-3, wherein R6For alkoxy.
5. the compound as any one of claim 1-4, wherein R7For unsubstituted alkyl.
6. compound as claimed in claim 1, wherein Y are
7. compound as claimed in claim 6, wherein Y are
8. the compound as any one of claim 1-7, wherein Z are-NR3R4。
9. the compound as any one of claim 1-8, wherein R3For hydrogen, and R4For H or substituted or unsubstituted alkane Base.
10. compound as claimed in any one of claims 1-9 wherein, wherein X are-N (R5)-。
11. the R in compound as claimed in claim 10, wherein adjacent atom1And R5The atom one that group is attached together with them Rise and form substituted or unsubstituted heterocycloalkyl.
12. compound as claimed in claim 11, wherein the heterocycloalkyl be substituted or unsubstituted pyrrolidine ring, Substituted or unsubstituted piperidine ring, or substituted or unsubstituted piperazine ring.
13. compound as claimed in claim 11, wherein the heterocycloalkyl be unsubstituted pyrrolidine ring, it is unsubstituted Piperidine ring, or unsubstituted piperazine ring.
14. compound as claimed in claim 11, it has following structure：
15. compound as claimed in claim 10, wherein R5For hydrogen.
16. compound as claimed in claim 10, wherein R5For substituted or unsubstituted alkyl.
17. compound as claimed in claim 16, wherein R5For unsubstituted alkyl.
18. compound as claimed in claim 17, wherein R5For-CH3。
19. compound as claimed in claim 16, wherein R5For substituted alkyl.
20. compound as claimed in claim 19, wherein R5For-CH2CH2NH2。
21. compound as claimed in claim 19, wherein R5For-CH2CH2NH (alkyl).
22. the compound as any one of claim 1-5, wherein X are-O-.
23. the compound as any one of claim 1-5, wherein X are-C (R1)(R2)-。
24. the compound as any one of claim 1-23, wherein n are 2 to 6 integer.
25. the compound as any one of claim 1-23, wherein n are 2.
26. the compound as any one of claim 1-23, wherein n are 3.
27. the compound as any one of claim 1-23, wherein n are 4.
28. compound as claimed in claim 1, it has formula (II) structure：
Wherein：
Z is-NR3R4；
N is 2 to 10 integer.
29. compound as claimed in claim 28, wherein Y areR6Independently selected from hydrogen, halogen ,- CN、-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkane Base, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, virtue Base sulfoxide, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For substituted or unsubstituted alkyl.
30. compound as claimed in claim 29, wherein R7For unsubstituted alkyl or it is selected from one or more bases of the following group The alkyl of group's substitution：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2、-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkane Base, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, Arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.
31. the compound as any one of claim 28-30, wherein R6For alkoxy.
32. the compound as any one of claim 28-31, wherein R7For unsubstituted alkyl.
33. compound as claimed in claim 28, wherein Y are
34. compound as claimed in claim 33, it has formula (IIa) structure：
Wherein：
P is 1 to 9 integer.
35. compound as claimed in claim 34, it has formula (IIaa) structure：
36. compound as claimed in claim 33, it has formula (IIb) structure：
Wherein：
P is 1 to 9 integer.
37. compound as claimed in claim 36, it has formula (IIbb) structure：
38. the compound as any one of claim 34-37, wherein p are 1.
39. the compound as any one of claim 34-37, wherein p are 2.
40. the R in the compound as any one of claim 28-39, wherein adjacent atom1And R5Group is together with them The atom of attachment forms substituted or unsubstituted heterocycloalkyl together.
41. compound as claimed in claim 40, wherein the heterocycloalkyl be substituted or unsubstituted pyrrolidine ring, Substituted or unsubstituted piperidine ring, or substituted or unsubstituted piperazine ring.
42. the compound as any one of claim 28-41, wherein R3For hydrogen, and R4For hydrogen or methyl.
43. compound as claimed in claim 42, wherein R4For hydrogen.
44. compound as claimed in claim 42, wherein R4For methyl.
45. compound as claimed in claim 1, it has formula (III) structure：
46. compound as claimed in claim 45, wherein Y areR6Independently selected from hydrogen, halogen ,- CN、-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2,-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkyl, cycloalkyl, fluoroalkyl, miscellaneous alkane Base, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, arylthio, alkyl sulfoxide, virtue Base sulfoxide, alkyl sulfone and aryl sulfone；J is-NHC (O) R7Or-C (O) OR7；And R7For substituted or unsubstituted alkyl.
47. compound as claimed in claim 46, wherein R7For unsubstituted alkyl or it is selected from one or more bases of the following group The alkyl of group's substitution：Halogen ,-CN ,-NH2、-NH(CH3)、-N(CH3)2、-OH、-CO2H、-CO2Alkyl ,-C (=O) NH2、-C (=O) NH (alkyl) ,-C (=O) N (alkyl)2,-S (=O)2NH2,-S (=O)2NH (alkyl) ,-S (=O)2N (alkyl)2, alkane Base, cycloalkyl, fluoroalkyl, miscellaneous alkyl, alkoxy, Fluoroalkyloxy, Heterocyclylalkyl, aryl, heteroaryl, aryloxy group, alkylthio, Arylthio, alkyl sulfoxide, aryl sulfoxid es, alkyl sulfone and aryl sulfone.
48. the compound as any one of claim 45-47, wherein R6For alkoxy.
49. the compound as any one of claim 45-48, wherein R7For unsubstituted alkyl.
50. compound as claimed in claim 45, wherein Y are
51. compound as claimed in claim 50, it has formula (IIIa) structure：
Wherein：
P is 0 to 9 integer.
52. compound as claimed in claim 51, it has formula (IIIaa) structure：
53. compound as claimed in claim 50, it has formula (IIIb) structure：
Wherein：
P is 0 to 9 integer.
54. compound as claimed in claim 53, it has formula (IIIbb) structure：
55. the compound as any one of claim 51-54, wherein p are 0.
56. the compound as any one of claim 51-54, wherein p are 1.
57. the compound as any one of claim 51-54, wherein p are 2.
58. the compound as any one of claim 45-57, wherein each R1With each R2It is hydrogen.
59. the compound as any one of claim 45-57, wherein at least one R1For substituted or unsubstituted alkyl.
60. compound as claimed in claim 1 or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or water Compound, it has following structure：
61. a kind of pharmaceutical composition, its include as compound claimed any one of claim 1-60 or its pharmaceutically Acceptable salt, pharmaceutically acceptable solvate or hydrate, and pharmaceutically acceptable diluent, excipient or viscous Mixture.
62. a kind of method for the pain for treating subject, it includes applying the claim of therapeutically effective amount to the subject Compound or its pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate any one of 1-60.
63. method as claimed in claim 62, wherein the compound any one of claim 1-60 or its pharmaceutically Acceptable salt, pharmaceutically acceptable solvate or hydrate local application, dermal administration, applied dermally or whole body are applied With.
64. method as claimed in claim 62, wherein the pain and postoperative pain, chronic postsurgical pain, nerve Pain, postherpetic neuralgia, diabetic neuropathy, HIV related neuropathies, complex region pain syndrome, cancer, Neurotrosis, cancer chemotherapy, Vulvodynia, wound, operation, chronic musculoskeletal pain, back pain, osteoarthritis or rheumatoid Arthritis is relevant.
CN201580074440.4A 2014-11-25 2015-11-24 Prodrugs of phenolic TRPV1 agonists Active CN107205961B (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201462084515P 2014-11-25 2014-11-25
US62/084,515 2014-11-25
US14/743,375 2015-06-18
US14/743,375 US9359316B1 (en) 2014-11-25 2015-06-18 Prodrugs of phenolic TRPV1 agonists
PCT/US2015/062531 WO2016086063A1 (en) 2014-11-25 2015-11-24 Prodrugs of phenolic trpv1 agonists

Publications (2)

Publication Number Publication Date
CN107205961A true CN107205961A (en) 2017-09-26
CN107205961B CN107205961B (en) 2021-03-16

Family

ID=56009519

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201580074440.4A Active CN107205961B (en) 2014-11-25 2015-11-24 Prodrugs of phenolic TRPV1 agonists

Country Status (28)

Country Link
US (1) US9359316B1 (en)
EP (2) EP3872063A1 (en)
JP (2) JP6670841B2 (en)
KR (1) KR102562571B1 (en)
CN (1) CN107205961B (en)
AR (1) AR102799A1 (en)
AU (1) AU2015353532B2 (en)
BR (1) BR112017010950B1 (en)
CA (1) CA2968061C (en)
CY (1) CY1124811T1 (en)
DK (1) DK3223805T3 (en)
EA (1) EA033619B1 (en)
ES (1) ES2871095T3 (en)
HK (1) HK1244672A1 (en)
HR (1) HRP20210775T1 (en)
HU (1) HUE054449T2 (en)
IL (1) IL252307B (en)
LT (1) LT3223805T (en)
MX (1) MX2017006818A (en)
PH (1) PH12017500974B1 (en)
PL (1) PL3223805T3 (en)
PT (1) PT3223805T (en)
RS (1) RS61875B1 (en)
SG (1) SG11201704290VA (en)
SI (1) SI3223805T1 (en)
TW (1) TWI692465B (en)
WO (1) WO2016086063A1 (en)
ZA (1) ZA201703409B (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112574061A (en) * 2019-09-30 2021-03-30 南京清普生物科技有限公司 TRPV1 agonist and preparation method and application thereof

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11634384B2 (en) 2014-11-25 2023-04-25 Concentric Analgesics, Inc. Prodrugs of phenolic TRPV1 agonists
JP2019516773A (en) * 2016-05-25 2019-06-20 コンセントリック アナルジジックス，インク． Prodrugs of phenol TRPV1 agonists in combination with local anesthetics and vasoconstrictors for improved local anesthesia
JP7100635B2 (en) 2016-11-02 2022-07-13 セントレクシオン セラピューティクス コーポレイション Stable aqueous capsaicin injection formulation and its medical use
CN108069898B (en) * 2016-11-16 2021-11-23 南华大学 Nicotinic acid-containing capsaicin ester derivative, preparation method and application thereof
WO2018217937A1 (en) * 2017-05-24 2018-11-29 Concentric Analgesics, Inc. Prodrugs of phenolic trpv1 agonists in combination with local anesthetics and vasoconstrictors for improved local anesthesia
AU2018302342A1 (en) 2017-07-20 2020-02-06 Centrexion Therapeutics Corporation Methods and compositions for treatment of pain using capsaicin
CN113166051A (en) 2018-07-27 2021-07-23 同心镇痛药物公司 Pegylated prodrugs of phenolic TRPV1 agonists
WO2020023793A1 (en) * 2018-07-27 2020-01-30 Concentric Analgesics, Inc. Pegylated prodrugs of phenolic trpv1 agonists
US11254659B1 (en) 2019-01-18 2022-02-22 Centrexion Therapeutics Corporation Capsaicinoid prodrug compounds and their use in treating medical conditions
US11447444B1 (en) 2019-01-18 2022-09-20 Centrexion Therapeutics Corporation Capsaicinoid prodrug compounds and their use in treating medical conditions
WO2021034863A1 (en) * 2019-08-19 2021-02-25 Chorda Pharma, Inc. Chemical derivatives and methods for synthesizing and compounding chemical derivatives related to capsaicin palmitate and capsaicin prodrugs
WO2022132650A1 (en) * 2020-12-14 2022-06-23 Concentric Analgesics, Inc. Prodrug of a phenolic trpv1 agonist for the treatment of pain
AR124337A1 (en) * 2020-12-14 2023-03-15 Concentric Analgesics Inc PHARMACEUTICAL FORMULATIONS OF A TRPV1 AGONIST PHENOLIC PRODRUG

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5094782A (en) * 1990-12-24 1992-03-10 National Science Council Of Republic Of China Synthesis of capsacin derivatives and their use as an analgesic drug and vessel dilation drug
CN101208294A (en) * 2005-04-25 2008-06-25 纽罗吉斯克斯公司 TRPV1 agonist compounds and methods for making and using the same

Family Cites Families (82)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3598122A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3598123A (en) 1969-04-01 1971-08-10 Alza Corp Bandage for administering drugs
US3993073A (en) 1969-04-01 1976-11-23 Alza Corporation Novel drug delivery device
US3710795A (en) 1970-09-29 1973-01-16 Alza Corp Drug-delivery device with stretched, rate-controlling membrane
US4069307A (en) 1970-10-01 1978-01-17 Alza Corporation Drug-delivery device comprising certain polymeric materials for controlled release of drug
US3731683A (en) 1971-06-04 1973-05-08 Alza Corp Bandage for the controlled metering of topical drugs to the skin
US3996934A (en) 1971-08-09 1976-12-14 Alza Corporation Medical bandage
US3742951A (en) 1971-08-09 1973-07-03 Alza Corp Bandage for controlled release of vasodilators
BE795384A (en) 1972-02-14 1973-08-13 Ici Ltd DRESSINGS
US3921636A (en) 1973-01-15 1975-11-25 Alza Corp Novel drug delivery device
US3993072A (en) 1974-08-28 1976-11-23 Alza Corporation Microporous drug delivery device
US4151273A (en) 1974-10-31 1979-04-24 The Regents Of The University Of California Increasing the absorption rate of insoluble drugs
US3972995A (en) 1975-04-14 1976-08-03 American Home Products Corporation Dosage form
US4077407A (en) 1975-11-24 1978-03-07 Alza Corporation Osmotic devices having composite walls
US4031894A (en) 1975-12-08 1977-06-28 Alza Corporation Bandage for transdermally administering scopolamine to prevent nausea
US4060084A (en) 1976-09-07 1977-11-29 Alza Corporation Method and therapeutic system for providing chemotherapy transdermally
US4201211A (en) 1977-07-12 1980-05-06 Alza Corporation Therapeutic system for administering clonidine transdermally
JPS5562012A (en) 1978-11-06 1980-05-10 Teijin Ltd Slow-releasing preparation
US4230105A (en) 1978-11-13 1980-10-28 Merck & Co., Inc. Transdermal delivery of drugs
US4229447A (en) 1979-06-04 1980-10-21 American Home Products Corporation Intraoral methods of using benzodiazepines
CA1146866A (en) 1979-07-05 1983-05-24 Yamanouchi Pharmaceutical Co. Ltd. Process for the production of sustained release pharmaceutical composition of solid medical material
US4291015A (en) 1979-08-14 1981-09-22 Key Pharmaceuticals, Inc. Polymeric diffusion matrix containing a vasodilator
US4327725A (en) 1980-11-25 1982-05-04 Alza Corporation Osmotic device with hydrogel driving member
US4476116A (en) 1982-12-10 1984-10-09 Syntex (U.S.A.) Inc. Polypeptides/chelating agent nasal compositions having enhanced peptide absorption
US5116817A (en) 1982-12-10 1992-05-26 Syntex (U.S.A.) Inc. LHRH preparations for intranasal administration
US4596795A (en) 1984-04-25 1986-06-24 The United States Of America As Represented By The Secretary, Dept. Of Health & Human Services Administration of sex hormones in the form of hydrophilic cyclodextrin derivatives
US4624848A (en) 1984-05-10 1986-11-25 Ciba-Geigy Corporation Active agent containing hydrogel devices wherein the active agent concentration profile contains a sigmoidal concentration gradient for improved constant release, their manufacture and use
JPS624233A (en) 1985-07-01 1987-01-10 Toyobo Co Ltd Production of histogenous plasminogen activator
GB8518301D0 (en) 1985-07-19 1985-08-29 Fujisawa Pharmaceutical Co Hydrodynamically explosive systems
JPH0778017B2 (en) 1985-12-28 1995-08-23 住友製薬株式会社 Pulsed and sustained release formulation
US4755386A (en) 1986-01-22 1988-07-05 Schering Corporation Buccal formulation
US5312325A (en) 1987-05-28 1994-05-17 Drug Delivery Systems Inc Pulsating transdermal drug delivery system
US4812590A (en) * 1987-06-25 1989-03-14 Merck & Co., Inc. Carbamates of 4-hydroxyanisole as prodrugs for chemotherapy of melanoma
US4968509A (en) 1987-07-27 1990-11-06 Mcneilab, Inc. Oral sustained release acetaminophen formulation and process
IL92966A (en) 1989-01-12 1995-07-31 Pfizer Dispensing devices powered by hydrogel
US5739136A (en) 1989-10-17 1998-04-14 Ellinwood, Jr.; Everett H. Intraoral dosing method of administering medicaments
US5017381A (en) 1990-05-02 1991-05-21 Alza Corporation Multi-unit pulsatile delivery system
US5633009A (en) 1990-11-28 1997-05-27 Sano Corporation Transdermal administration of azapirones
ES2111065T5 (en) 1991-04-16 2005-06-16 Nippon Shinyaku Company, Limited PROCEDURE TO PRODUCE A SOLID DISPERSION.
JPH0778037B2 (en) * 1991-06-13 1995-08-23 ナショナル サイエンス カウンシル Analgesics and vasodilators containing a capsaicin derivative or its acid ester as an active ingredient
US5229135A (en) 1991-11-22 1993-07-20 Prographarm Laboratories Sustained release diltiazem formulation
HU227530B1 (en) 1991-11-22 2011-07-28 Warner Chilcott Company Delayed-release compositions containing risedronate and process for their production
US5340591A (en) 1992-01-24 1994-08-23 Fujisawa Pharmaceutical Co., Ltd. Method of producing a solid dispersion of the sparingly water-soluble drug, nilvadipine
US5461140A (en) 1992-04-30 1995-10-24 Pharmaceutical Delivery Systems Bioerodible polymers for solid controlled release pharmaceutical compositions
US5260068A (en) 1992-05-04 1993-11-09 Anda Sr Pharmaceuticals Inc. Multiparticulate pulsatile drug delivery system
US5281420A (en) 1992-05-19 1994-01-25 The Procter & Gamble Company Solid dispersion compositions of tebufelone
AU4198793A (en) 1992-07-24 1994-01-27 Takeda Chemical Industries Ltd. Microparticle preparation and production thereof
US5700485A (en) 1992-09-10 1997-12-23 Children's Medical Center Corporation Prolonged nerve blockade by the combination of local anesthetic and glucocorticoid
JP2616252B2 (en) 1992-10-16 1997-06-04 日本新薬株式会社 Preparation of wax matrix
US5260069A (en) 1992-11-27 1993-11-09 Anda Sr Pharmaceuticals Inc. Pulsatile particles drug delivery system
US5686105A (en) 1993-10-19 1997-11-11 The Procter & Gamble Company Pharmaceutical dosage form with multiple enteric polymer coatings for colonic delivery
US5665378A (en) 1994-09-30 1997-09-09 Davis; Roosevelt Transdermal therapeutic formulation
US5567441A (en) 1995-03-24 1996-10-22 Andrx Pharmaceuticals Inc. Diltiazem controlled release formulation
KR19990014865A (en) 1995-05-17 1999-02-25 피터 이. 브래이브맨 Compositions containing fatty acids to enhance digestion and absorption in the small intestine
SE9502244D0 (en) 1995-06-20 1995-06-20 Bioglan Ab A composition and a process for the preparation thereof
US5837284A (en) 1995-12-04 1998-11-17 Mehta; Atul M. Delivery of multiple doses of medications
US5858401A (en) 1996-01-22 1999-01-12 Sidmak Laboratories, Inc. Pharmaceutical composition for cyclosporines
US6923983B2 (en) 1996-02-19 2005-08-02 Acrux Dds Pty Ltd Transdermal delivery of hormones
US6929801B2 (en) 1996-02-19 2005-08-16 Acrux Dds Pty Ltd Transdermal delivery of antiparkinson agents
US6458373B1 (en) 1997-01-07 2002-10-01 Sonus Pharmaceuticals, Inc. Emulsion vehicle for poorly soluble drugs
EP1201241B8 (en) 1997-03-13 2010-10-27 James N. Campbell Compositions containing capsaicin or capsaicin analogues and an anesthetic
US5840329A (en) 1997-05-15 1998-11-24 Bioadvances Llc Pulsatile drug delivery system
US6391452B1 (en) 1997-07-18 2002-05-21 Bayer Corporation Compositions for nasal drug delivery, methods of making same, and methods of removing residual solvent from pharmaceutical preparations
US5869090A (en) 1998-01-20 1999-02-09 Rosenbaum; Jerry Transdermal delivery of dehydroepiandrosterone
US6946144B1 (en) 1998-07-08 2005-09-20 Oryxe Transdermal delivery system
ES2307482T3 (en) 1999-02-10 2008-12-01 Pfizer Products Inc. SOLID PHARMACEUTICAL DISPERSIONS.
US6395300B1 (en) 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
EP1341795A2 (en) * 2000-10-10 2003-09-10 Ortho-McNeil Pharmaceutical, Inc. Novel labeled resiniferatoxin derivatives
US6465014B1 (en) 2001-03-21 2002-10-15 Isp Investments Inc. pH-dependent sustained release, drug-delivery composition
US6960563B2 (en) 2001-08-31 2005-11-01 Morton Grove Pharmaceuticals, Inc. Spontaneous emulsions containing cyclosporine
US20050058734A1 (en) 2002-12-18 2005-03-17 Algorx Administration of capsaicinoids
MXPA05006670A (en) 2002-12-18 2005-10-19 Algorx Pharmaceuticals Inc Administration of capsaicinoids.
US20040202735A1 (en) * 2003-04-08 2004-10-14 Moore Bob M. Method and kit for controlling bleeding
EP1863536A4 (en) 2005-03-14 2011-07-20 Univ Alberta Synthetic anti-candida albicans oligosaccharide based vaccines
US7943666B2 (en) 2006-07-24 2011-05-17 Trinity Laboratories, Inc. Esters of capsaicin for treating pain
JP2010529039A (en) 2007-05-30 2010-08-26 ブリガム・ヤング・ユニバーシティ Protein kinase binding nucleosides and related methods
US8535655B2 (en) 2008-10-10 2013-09-17 Polyactiva Pty Ltd. Biodegradable polymer—bioactive moiety conjugates
JP5746629B2 (en) * 2008-10-10 2015-07-08 ポリアクティヴァ・プロプライエタリー・リミテッド Biodegradable polymer-bioactive moiety complex
CN101774938B (en) * 2010-01-20 2014-04-30 中国药科大学 Type of capsaicine derivative, preparation method thereof and medical use for preparing new analgesic thereof
US9492409B2 (en) 2012-05-23 2016-11-15 Cellix Bio Private Limited Compositions and methods for the treatment of local pain
KR101478520B1 (en) * 2014-01-24 2015-01-02 동신대학교산학협력단 Capsaicin-Peptide Having Improved Safety for Skin and Cosmetic External Preparation Composition for Skin Using the Same
CN104447777B (en) * 2014-11-26 2016-09-14 浙江大学 A kind of capsaicin-camptothecin cancer therapy drug conjugate and its preparation method and application

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5094782A (en) * 1990-12-24 1992-03-10 National Science Council Of Republic Of China Synthesis of capsacin derivatives and their use as an analgesic drug and vessel dilation drug
CN101208294A (en) * 2005-04-25 2008-06-25 纽罗吉斯克斯公司 TRPV1 agonist compounds and methods for making and using the same

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
梅旭辉: "《中国执业药师手册》", 31 January 2002, 湖北科学技术出版社 *
陆智杰，俞卫锋: "《内脏痛 基础与临床》", 31 August 2013, 人民军医出版社 *
高昆玉: "《色谱法在精细化工中的应用》", 30 November 1997, 中国石化出版社 *
黎明江，黄鹤，吴钢: "《瞬时受体电位离子通道：生理功能与疾病》", 30 November 2007, 湖北科学技术出版社 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112574061A (en) * 2019-09-30 2021-03-30 南京清普生物科技有限公司 TRPV1 agonist and preparation method and application thereof
WO2021063373A1 (en) * 2019-09-30 2021-04-08 南京清普生物科技有限公司 Trpv1 agonist and preparation method therefor and use thereof
CN112574061B (en) * 2019-09-30 2023-05-19 南京清普生物科技有限公司 TRPV1 agonist and preparation method and application thereof

Also Published As

Publication number Publication date
ZA201703409B (en) 2023-10-25
EP3223805B1 (en) 2021-02-24
DK3223805T3 (en) 2021-05-25
TW201629004A (en) 2016-08-16
EA033619B1 (en) 2019-11-11
JP2020114813A (en) 2020-07-30
US20160145225A1 (en) 2016-05-26
EP3872063A1 (en) 2021-09-01
ES2871095T3 (en) 2021-10-28
IL252307B (en) 2021-02-28
JP2017536416A (en) 2017-12-07
PH12017500974A1 (en) 2018-01-08
CA2968061C (en) 2023-08-22
KR102562571B1 (en) 2023-08-01
SI3223805T1 (en) 2021-09-30
EP3223805A1 (en) 2017-10-04
HK1244672A1 (en) 2018-08-17
HRP20210775T1 (en) 2021-06-25
JP6670841B2 (en) 2020-03-25
AU2015353532A1 (en) 2017-06-15
HUE054449T2 (en) 2021-09-28
BR112017010950B1 (en) 2023-12-26
CN107205961B (en) 2021-03-16
KR20170095896A (en) 2017-08-23
PL3223805T3 (en) 2021-10-11
BR112017010950A2 (en) 2018-07-03
EA201790896A1 (en) 2017-12-29
IL252307A0 (en) 2017-07-31
US9359316B1 (en) 2016-06-07
AU2015353532B2 (en) 2021-03-18
SG11201704290VA (en) 2017-06-29
CY1124811T1 (en) 2022-11-25
EP3223805A4 (en) 2018-07-25
LT3223805T (en) 2021-06-10
WO2016086063A1 (en) 2016-06-02
RS61875B1 (en) 2021-06-30
PH12017500974B1 (en) 2018-01-08
MX2017006818A (en) 2018-01-30
CA2968061A1 (en) 2016-06-02
JP7026152B2 (en) 2022-02-25
TWI692465B (en) 2020-05-01
AR102799A1 (en) 2017-03-22
PT3223805T (en) 2021-05-28

Similar Documents

Publication Publication Date Title
CN107205961A (en) The prodrug of phenols TRPV1 activators
CN103635179B (en) The improved parenteral formulation of lipophilic pharmaceutical agent and preparation and use its method
US10851123B2 (en) Prodrugs of phenolic TRPV1 agonists
CN109562281A (en) The prodrug of phenols TRPV1 agonist is combined with local anesthetic and vasoconstrictor for improving local anaesthesia
CN102497864A (en) Sigma ligands for the prevention or treatment of pain induced by chemotherapy
CA2781436A1 (en) Arachidonic acid analogs and methods for analgesic treatment using same
CN107438613A (en) The Compounds and methods for dead for preventing or treating sensory hair cell
US11634384B2 (en) Prodrugs of phenolic TRPV1 agonists
TW202019887A (en) Pegylated prodrugs of phenolic trpv1 agonists
KR20150109456A (en) Protopanoxadiol derivative, preparation method thereof and application thereof
EP3409664B1 (en) Application of substituted cinnamamide derivatives in preparation of anti-anxiety medications
WO2020023793A1 (en) Pegylated prodrugs of phenolic trpv1 agonists
US6593331B2 (en) Method for treatment of pain
US20170260131A1 (en) Prodrugs of phenolic trpv1 agonists
CA3062452A1 (en) Compositions, combinations, and methods thereof for treatment of neurological disorders
CN105777520A (en) Novel chalcone compound Chalcone-1203, and composition, preparation method and application thereof
JP2013503908A (en) Compounds for treating disorders or diseases associated with neurokinin 2 receptor activity
CN101910132A (en) Novel piperidine-4-carboxylic acid phenyl-alkyl-amide derivatives and their use as monoamine neurotransmitter re-uptake inhibitors
CN1822837A (en) 2-methoxymethyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane tartrate salts
US20230100890A1 (en) Use of combined inhalant cannabinoid therapy in the treatment of migraine
CN101648891B (en) Aryl cyclobutyl compound and application thereof in preparing weight-losing medicine
WO1996031482A1 (en) Novel heterocyclic compounds
WO1996031483A1 (en) Novel heterocyclic compounds

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1244672

Country of ref document: HK

GR01 Patent grant
GR01 Patent grant